A comprehensive review on the potential therapeutic benefits of phosphodiesterase inhibitors on cardiovascular diseases

Biomedicine & Pharmacotherapy 94 (2017) 541–556

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Review

A comprehensive review on the potential therapeutic benefits of phosphodiesterase inhibitors on cardiovascular diseases Reza Shafiee-Nicka,b , Amir R. Afsharia,b , Seyed Hadi Mousavic, Abbasali Rafighdoustd , Vahid Reza Askarib , Hamid Mollazadehe, Sahar Fanoudib , Elmira Mohtashamif , Vafa Baradaran Rahimib , Moein Mohebbig , Mohammad Mahdi Vahedib,h,* a

Pharmacological Research Center of Medicinal Plants, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran Department of Pharmacology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran c Medical Toxicology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran d Department of Cardiology, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran e Department of Physiology and Pharmacology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran f Department of Pharmacodynamic and Toxicology, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran g Department of Internal Medicine, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran h Health Promotion Research Center, Zahedan University of Medical Sciences, Zahedan, Iran b

A R T I C L E I N F O

Article history: Received 22 April 2017 Received in revised form 2 July 2017 Accepted 19 July 2017 Keywords: Phosphodiesterase Cardiovascular disease Potential therapeutic Phosphodiesterase inhibitors

A B S T R A C T

Phosphodiesterases are a group of enzymes that hydrolyze cyclic nucleotides, which assume a key role in directing intracellular levels of the second messengers' cAMP and cGMP, and consequently cell function. The disclosure of 11 isoenzyme families and our expanded knowledge of their functions at the cell and molecular level stimulate the improvement of isoenzyme selective inhibitors for the treatment of various diseases, particularly cardiovascular diseases. Hence, future and new mechanistic investigations and carefully designed clinical trials could help reap additional benefits of natural/synthetic PDE inhibitors for cardiovascular disease in patients. This review has concentrated on the potential therapeutic benefits of phosphodiesterase inhibitors on cardiovascular diseases. © 2017 Elsevier Masson SAS. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . Phosphodiesterase . . . . . . . . . . . . . . . . . . . Methods of search . . . . . . . . . . . . . . . . . . . PDE inhibitors . . . . . . . . . . . . . . . . . . . . . . PDE1 . . . . . . . . . . . . . . . . . . . . . . . 4.1. Overview . . . . . . . . . . . . 4.1.1. Cardio-protection effects 4.1.2. 4.2. PDE2 . . . . . . . . . . . . . . . . . . . . . . . Overview . . . . . . . . . . . . 4.2.1. 4.2.2. Cardio-protection effects PDE3 . . . . . . . . . . . . . . . . . . . . . . . 4.3. 4.3.1. Overview . . . . . . . . . . . . Cardio-protection effects 4.3.2. 4.4. PDE4 . . . . . . . . . . . . . . . . . . . . . . . Overview . . . . . . . . . . . . 4.4.1. Cardio-protection effects 4.4.2. PDE5 . . . . . . . . . . . . . . . . . . . . . . . 4.5.

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* Corresponding author at: Department of Pharmacology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. E-mail address: [email protected] (M.M. Vahedi). http://dx.doi.org/10.1016/j.biopha.2017.07.084 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.

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5. 6.

R. Shafiee-Nick et al. / Biomedicine & Pharmacotherapy 94 (2017) 541–556

4.5.1. Overview . . . . . . . . . . . . Cardio-protection effects 4.5.2. PDE6 . . . . . . . . . . . . . . . . . . . . . . . 4.6. Overview . . . . . . . . . . . . 4.6.1. Cardio-protection effects 4.6.2. PDE7 . . . . . . . . . . . . . . . . . . . . . . . 4.7. Overview . . . . . . . . . . . . 4.7.1. Cardio-protection effects 4.7.2. 4.8. PDE8 . . . . . . . . . . . . . . . . . . . . . . . Overview . . . . . . . . . . . . 4.8.1. Cardio-protection effects 4.8.2. 4.9. PDE9 . . . . . . . . . . . . . . . . . . . . . . . Overview . . . . . . . . . . . . 4.9.1. Cardio-protection effects . . . . . . . 4.10. PDE10 . . . . . . . . . . . . . . . . . . . . . . 4.11. 4.11.1. Overview . . . . . . . . . . . . Cardio-protection effects 4.11.2. PDE11 . . . . . . . . . . . . . . . . . . . . . . . 4.12. Overview . . . . . . . . . . . . 4.12.1. 4.12.2. Cardio-protection effects Natural PDE inhibitors . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . Conflict of interests . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Nowadays, despite a variety of therapeutic advances, cardiovascular disease (CVD) remains a leading cause of mortality worldwide [1,2]. CVD is a category of diseases that involves the heart or blood vessels such as coronary artery diseases (CAD) like angina and myocardial infarction. To treat cardiac or vascularrelated diseases many family-selective PDE inhibitors are used clinically or pre-clinically [3,4]. The cyclic nucleotides, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP) are basic components and act as mediators of signal transduction cascades in numerous cell types throughout the body. Within the cardiomyocyte, cAMP and cGMP play numerous and usually antagonistic roles, both physiologically and pathologically. In addition, acute and chronic cyclic nucleotide signaling can have divergent effects [5]. For example, b-adrenergic produced cAMP increases cardiac contractile force and pace-making, while initiation of certain cGMP pools antagonize this. Chronic stimulation of b-adrenergic receptors is related to the development of maladaptive cardiac remodeling, fibrosis, and cardiac myocyte caspase-mediated cell death, whereas the chronic cGMP signal will attenuate these same effects and preserve cardiac function. Lately, there has been much enthusiasm for identifying new clinical uses of PDE inhibitors (inodilators, agents with both positive inotropic and vasodilator effects) in numerous infirmities including CVD [6]. Thus, the aim of this review is to spotlight the potential advantages of PDE inhibitors in CVD in clinical trials and in vivo models. We have searched the scientific databases: PubMed, Web of Science, and Google Scholar using the keywords: PDE; PDE inhibitors; cardiovascular diseases; pulmonary hypertension; and heart failure (HF) between years 1975 to 2017. We have also summarized the current scientific information about the cardio-protective activities of PDE inhibitors and their mechanisms of action. 2. Phosphodiesterase A phosphodiesterase (PDE) refers to cyclic nucleotide phosphodiesterases (PDEs), which have great clinical significance. There are also several alternative families of PDEs, as well as phospholipases C and D, autotaxin, sphingomyelin PDE, DNases,

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RNases, and restriction endonucleases, as well as numerous lesswell-characterized small-molecule PDEs. The cyclic nucleotide PDEs comprise of a group of enzymes that degrade the phosphodiester bond within the second messenger molecules cAMP and cGMP. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains [7–9]. The cAMP- and cGMP-signaling systems that are balanced by adenylate cyclase and guanylate cyclase are involved in several physiological processes, including visual transduction and reproduction, vascular resistance, cardiac output, cell proliferation and differentiation, gene expression, inflammation and immune response, apoptosis and metabolic pathways such as steroidogenesis, insulin secretion, and glycogen synthesis, additionally as glycogenolysis, lipolysis, and lipogenesis. Therefore, PDEs are important regulators of signal transduction mediated by these second messenger molecules [5,10–12]. The cAMP and cGMP transduce signal-encoded information as well as cAMP- or cGMP activated protein kinases [protein kinase A or G (PKA or PKG), respectively], cyclic nucleotide-gated ion channels (leading to intracellular Ca2+ elevation), and exchange proteins are directly activated by cAMP (EPAC) and hydrolyzed by different PDE isoenzymes [13–15]. PDE inhibitors have various pharmacological properties that include anti-inflammatory, anti-oxidant, vasodilator, cardio-tonic and anti-cancer as well as being a memory enhancer. Thus, they can be used as therapeutic agents for many diseases such as asthma, chronic obstructive pulmonary disease, erectile dysfunction, depression, dementia, Parkinson's disease, pulmonary hypertension (PHT) and HF [16–26]. The superfamily of PDEs are classified into eleven based on structure, localization, gene expression, protein, and pharmacological properties, and endogenous and exogenous regulators [27,28]. The substrate and regulators of PDEs are given [13,14] in Table 1. Some of these enzymes hydrolyze only cAMP or cGMP or mix specificity and are listed in Fig. 1 [15,29,30]. 3. Methods of search This research included articles from 1975 to 2017 that were found in the electronic databases: PubMed, Science Direct, Scopus,

R. Shafiee-Nick et al. / Biomedicine & Pharmacotherapy 94 (2017) 541–556

543

Table 1 The superfamily, regulatory mechanism (s) and localization of PDEs. Family

Substrate Regulatory mechanism (s)

Localization

PDE1

CaM activated

Blood vessels, vascular tissue, heart, lung, testes, platelets and lymphocytes

Stimulated/activated by cGMP

Heart, brain, platelets, adrenal glomerulosa cells, endothelial cells and macrophages

cGMP-inhibited

PDE4

cAMP/ cGMP cAMP/ cGMP cAMP/ cGMP cAMP

PDE5

cGMP

cGMP-insensitive Phosphorylated by PKA Phosphorylated by ERK PKA/PKG phosphorylated

PDE6 PDE7

cGMP cAMP

Transducin-activated Rolipram-insensitive

PDE8 PDE9 PDE10

cAMP cGMP cAMP/ cGMP cAMP/ cGMP

Rolipram-insensitive IBMX-insensitive IBMX-insensitive Unknown

Platelets, kidney, vascular smooth muscle, heart, oocyte, adipocytes, hepatocytes, developing sperm, B cells, T-lymphocytes and macrophages Brain, smooth muscles, cardiovascular tissues, inflammatory cells, immune system and keratinocytes Aortic smooth muscle cells, heart, placenta, skeletal muscle, pancreas, brain, liver, lungs, platelet, corpus cavernosum and retina Retina PDE7A2 identified in human cardiac myocytes, PDE7A: B-lymphocytes PDE7B: Brain, heart, skeletal muscle and pancreas Testis, eye, liver, skeletal muscle, heart, kidney, ovary and brain Kidney, brain and heart Brain (in striatal medium spiny neurons), pineal gland and testis

Unknown

Brain (ventral hippocampus), prostate, testis, pituitary gland, liver and heart

PDE2 PDE3

PDE11

Abbreviations: CaM: Calcium-calmodulin; PKA: Protein kinase A; ERK: Extracellular signal regulated kinase; PKG: Protein kinase G; IBMX: 3-isobutyl-1-methylxanthine.

Web of Science, Scirus, and Google Scholar. The search words were: cardiovascular diseases, heart failure, pulmonary hypertension, phosphodiesterases, and phosphodiesterase inhibition. Only current articles that reported the effects of PDE inhibitors on cardiovascular diseases were included in our study. Next, an evaluation between PDE inhibition and its potential therapeutic benefits on cardiovascular diseases was done. 4. PDE inhibitors Pharmacological inhibition of PDEs has gained increased enthusiasm as a treatment strategy and drug development; hence, focusing on certain PDEs has the potential to ameliorate CVD. In this section, we have discussed the pharmacological PDE inhibitors and their implication in the treatment of CVD. 4.1. PDE1 4.1.1. Overview The PDE1 family is a vast family encoded by three distinct genes that are stimulated by the Ca2+-calmodulin (CaM, up to 10-fold or more) together with PDE1A, PDE1B, and PDE1C [31]. Their presence was recognized in blood vessels, vascular tissue, heart, lung, testes, platelets, and lymphocytes [32]. The initiation of the PDE1 by the calcium ions seems to be regulated via the phosphorylation process by the CaM-dependent-protein kinase

Fig. 1. Specificity of PDEs.

II [33,34]. CaM phosphorylation can cut back the selective activation of the CaM antagonists on PDE activity, whereas calcium-dependent activation can stay unaffected. The PDE1 inhibitors are viable vasodilators; however, they are diminished in activity in terms of platelet aggregation. These are antagonists of the CaM that reduce the PDE1 activity, while the other compounds interact specifically with the catalytic site of PDE1. The PDE1 role in the control of cAMP and medical management of Ca2+ and its role on the cGMP levels has been studied. It is crucial to differentiate the PDE1 by the PDE5, which also hydrolyzes the cGMP that is found within the fractions of PDE1 contaminated with PDE5 [35–37]. In vitro, PDE1A and PDE1B give the impression of having a high specificity for cGMP, whereas PDE1C has similar affinity for both cGMP and cAMP [38,39]. The foremost PDE1 inhibitors are nimodipine [40], vinpocetine [41], IC224 [42], phenothiazines, and SCH51866 [43]. Previously, researchers have realized the lack of information about the presence of PDEs in cardiac myocytes [44] and the nonattendance of specific inhibitors of PDE1 clarifies why there has been little examination of the impacts of PDE1 hindrance in models of CVD. PDE1C1 is expressed at high levels in human cardiac myocytes and it constitutes most of the cGMP-hydrolytic activity in human myocardium and a large extent the cAMPhydrolytic action within the soluble division of the human myocardium [45]. 4.1.2. Cardio-protection effects Some studies show that PDE1A and C have a major role in HF. PHT is connected with augmented vascular resistance because of sustained contraction and increased proliferation of pulmonary arterial smooth muscle cells (PASMC); the unusual tone and remodeling in the pulmonary vasculature may relate, at any rate, partially to diminished cyclic nucleotide levels. This study tested the hypothesis that PASMC isolated from patients with PHT, either with idiopathic pulmonary arterial hypertension (IPAH) or secondary pulmonary hypertension (SPH), have accumulated expression and activity of PDE isoforms that diminish the responsiveness of agents that raise cellular cAMP. The outcomes propose that a development in PDE isoforms, specifically PDE1C, adds to diminished cAMP and expanded multiplication of PASMC in patients with PHT. PDE1 isoforms may serve as pharmacological targets for the treatment of both primary and secondary forms of the disease [46].

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Schermuly et al. in their study has shown that PDE1 in pulmonary arterial hypertension (PAH) is upregulated. Additionally, semipermanent infusion of a PDE1 inhibitor reverses pulmonary hypertension, lung vascular remodeling, and right heart hypertrophy in monocrotaline-injected rats. So, it is suggested that PDE1A and C play a vital role in the structural remodeling process underlying the development of severe PHT and cardiopathy [47]. It has been shown in two studies that PDE1 inhibitors dilate coronary arteries and they are recommended for use in the treatment of angina pectoris and CAD [48,49]. Moreover, it can potentiate endothelial dependent vasorelaxation by upregulating the activity of the cGMP produced from NO activation of the guanylate cyclase [48] and antiplatelet and antithrombotic action that may presumably impact the different types of angina pectoris [50,51]. Nagel et al. has shown that PDE1A, a CaM-stimulated PDE preferentially hydrolyzing cGMP, is predominantly cytoplasmic in medial “contractile” vascular smooth muscle cells (VSMCs). Using essential VSMCs has shown that cytoplasmic and nuclear PDE1A are associated with a contracted marker (SM-calponin) and a development marker (Ki-67), separately. Diminishing PDE1A function considerably lessens VSMC development by decreasing proliferation via G1 arrest and causes apoptosis. Inhibiting PDE1A likewise prompts intracellular cGMP elevation, p27Kip1 upregulation, cyclin D1 downregulation, and p53 activation. In addition, cytoplasmic PDE1A regulates myosin light chain phosphorylation with little impact on apoptosis in sub-cultured VSMCs re-differentiated, whereas inhibiting nuclear PDE1A has the opposite effect. They have advised that PDE1A is critical in VSMC growth and survival, and could contribute to the neointima (a new or thickened layer of arterial intima shaped particularly on a prosthesis or in atherosclerosis by migration and proliferation of cells from the media) formation in CAD and restenosis [39]. PDE1A protein expression is considerably upregulated in hearts and cardiomyocytes from varied pathological hypertrophy animal models and in isolated neonatal and adult rat ventricular myocytes treated with neuro-humoral stimuli angiotensin II (Ang II) and isoproterenol [52]. Using IC86340, a selective PDE1 inhibitor reduces myocyte hypertrophy via activation of cGMP-dependent protein kinase in a hypertrophy mouse model induced by isoproterenol [38]. Crosswhite and Sun have shown that the inhibition of PDE1 attenuates cold-induce PHT by suppressing macrophage infiltration, NADPH oxidase activation and superoxide production, and reversed pulmonary artery remodeling [53]. 4.2. PDE2 4.2.1. Overview The PDE2 enzyme is one among 21 completely different PDEs found in mammals. There is just one gene family coding for the PDE2, which is the PDE2A. However, three splice variants have been identified: PDE2A1, PDE2A2 (found only in rats), and PDE2A3 [54]. The recognizing highlight of PDE2 is that it is allosterically fortified by cGMP binding to one of its GAF domains (a type of protein domain that is found in five members of the cyclic nucleotide PDE superfamily: PDE2, PDE5, and PDE6, which binds cGMP to the GAF domain, PDE10 which binds cAMP, and PDE11 which binds both cGMP and cAMP) [13,55]. PDE2 is expressed in a wide assortment of tissues and cell types including heart, brain, platelets, adrenal glomerulosa cells, endothelial cells, and macrophages [56]. The foremost PDE2 inhibitors are erythro-9-(2hydroxy-3-nonyl) adenine (EHNA) (MEP-1) [57], BAY 60-7550 [58], PDP [59], and IC933 [42]. 4.2.2. Cardio-protection effects A remarkable property of PDE2 is its capability to negotiate negative “cross talk” between the cGMP and cAMP pathways in

platelets. It is believed that elevated amounts of NO elicit high cGMP accumulation that activates PDE2 and reduces cAMP [60]. Cardiac myocytes are another cell type in which PDE2 is fortified by cGMP, and interplaying between PDE2 and PDE3 may occur. In physiological conditions, cAMP is produced by the initiation of b-adrenergic receptors in light of stress or activity. As an outcome, the heart yield rapidly increases through activation of PKA and its signal cascade. In disease conditions though, chronic elevation of cAMP leads to remodeling and cardiac hypertrophy. Strangely, and in clear disagreement with the harmful impact of the managed rise of cAMP, increments of a few parts of cAMP/PKA that act as a signaling, appears to help the failing heart that might be utilizing an antihypertrophic agent [61]. In human cardiac myocytes, PDE2 seems to be a controller of the cardiac L-type Ca2+ current. L-type Ca2+ channels are traditionally perceived as targets for activation by b-adrenergic receptor-stimulated cAMP and PKA, and modifications in channel activity have both chronotropic and ionotropic effects [62]. A review has shown that actuation of b3-adrenergic receptors activates PDE2 via the NO/cGMP pathway, leading to degradation of b1- and b2-produced cAMP in cardiomyocytes of mice. This PDE2 activation blunts isoproterenol-mediated contractility increments [63]. Another study has shown that the inhibition of PDE2 augments cGMP and cAMP signaling to ameliorate PHT, which subsequently elicits pulmonary dilation, prevents pulmonary vascular remodeling, and reduces the right ventricular hypertrophy (RVH) that is characteristic of PHT [64]. Bay 60-7550 (a PDE2 inhibitor) restores the capacity of B-type natriuretic peptide (BNP) to reduce [Ca2+]i in pre-hypertensive spontaneously hypertensive rats (SHRs). Overexpression of dnPDE2A (a catalytically-dead mutant of PDE2A) using a viral vector (Ad.CMVmCherry. dnPDE2A) also rescues the SHR inhibition of the calcium transients from the SHR. They have concluded that higher PDE2A expression in the SHR abolishes the capacity of BNP to reduce the release of neurotransmitters. They additionally have proposed that inhibiting neuronal PDE2 might be critical in restoring the efficacy of BNP to decrease sympathetic neurotransmission in cases of dys-autonomia [65]. A study has shown that PDE2 is up-regulated in human failing hearts and blunts b-adrenergic responses in cardiomyocytes. They presumed this may constitute an essential protective defense reaction during cardiac stress, for instance by antagonizing excessive b-AR drive [66]. Dittrich et al. in their study on regulation of the L-type Ca2+ current (ICa) by the two nitric oxide (NO) donors sodium nitroprusside has shown that in frog cardiomyocytes there is an incitement of guanylyl cyclase by NO. This prompts a powerful local depletion of cAMP near the Ltype Ca2+ channels due to the activation of PDE2, but only to a modest reduction of cAMP within the rest of the cell that might be utilized for CVD [67]. Further, Rivet-Bastide et al. concluded that basal ICa is controlled by PDE2 action in human atrial myocytes utilizing EHNA (a well-known inhibitor of adenosine deaminase) [68]. Yanaka et al. has shown that mRNA levels of PDE2 and its activity were deregulated in response to pressure overload in the heart of rat post-transcriptionally [52]. Vettel et al. has shown that PDE2 inhibition protects arrhythmia and preserves contractile function after myocardial infarction and contributes to heart rate regulation induced by catecholamine [69]. Likewise, they have presumed that PDE2A is particularly upregulated in human and experimental failing hearts and this may constitute an imperative resistance mechanism during cardiac stress, by antagonizing the cAMP-mediated toxic effects [70]. The A-kinase anchor proteins (AKAPs) are a gathering of different proteins that bind other components including: PDEs which catalyzes the hydrolysis of cAMP, phosphatases which dephosphorylate downstream PKA targets, and the other kinases

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(PKC and mitogen-activated protein kinase) in which there are PKA-AKAP association alternations in HF. An increased amount of AKAP-bound PDE2 has been accounted for in HF. Thus, the binding of PDE2 by AKAP may keep PDE2 from hydrolyzing cyclic nucleotides, which could contribute to the pathology of HF [71]. Given the essential roles of PDE2 in myocyte cGMP and cAMP compartmentation, the potential therapeutic effects of focusing on myocardial PDE2 are still yet to be resolved. 4.3. PDE3 4.3.1. Overview PDE3 is frequently alluded to as the cGMP-inhibited PDE, as under certain conditions, PDE3 seems to assume a basic part in the cGMP-dependent potentiation of cAMP signaling and they additionally are recognized by their capacity to be actuated by several phosphorylation pathways including the PKA and phosphoinositide-3 kinase (PI3K)/protein kinase B (PKB) pathways [72,73]. The PDE3 family in mammals consists of two members, PDE3A and PDE3B, and the isoforms have fundamentally similar pharmacological and kinetic properties; however, the distinction is in expression profiles and the affinity for cGMP [74–76]. PDE3A exists in the platelets, kidney, vascular smooth muscle, heart, and oocyte. Studies have shown that the expression of PDE3A is deregulated in some CADs [77,78]. In addition, PDE3B is localized in the adipocytes, hepatocytes, vascular smooth muscle, developing sperm, kidney, B cells, T-lymphocytes, and macrophages. The selective PDE3 inhibitors are mostly used as inotropic drugs and currently are utilized in the treatment of patients with cardiopathy through raising intracellular cAMP content in cardiac myocytes. PDE3 inhibitors include: cilostamide (first potent selective inhibitor of cAMP-PDE in the platelets), cilostazol, anagrelide, enoxamone, amrinone, milrinone, vesnarinone, siguazodan, olprinone, motapizone, pimobendan, imadazodan, piroximone, CI-930, 6-(benzyloxy)-4-methylquinolin-2(1H)-one, 6-[4-(4-methylpiperidin-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1H)-one, MC2, sulmazole, and trequinsin [73,78–85]. 4.3.2. Cardio-protection effects PDE3 is mostly used for a new muscle contract inducer drug and currently is used in the treatment of patients with cardiopathy through raising intracellular cAMP content in cardiac myocytes [86]. Besides, PDE3 inhibitors raise myocardial contractility temporarily. Nonetheless, their long term administration results in an increase in cardiovascular mortality [87–89]. In this way, PDE3 assumes a motivating part in cardiovascular contraction by balancing Ca2+ entry consecutively to cAMPdependent phosphorylation of the voltage-gated Ca2+ channel [90]. Also, inhibition of PDE3 activity seems to be the mechanism by which NO stimulates renin release from the kidney [91–93]. In such a manner, Vandecasteele et al. has shown that the inhibition of PDE3 activity increases L-type Ca2+ currents in cardiomyocytes isolated from human, frog, and rat hearts and accordingly, exhibits their potential benefit in treating HF by positive inotropic effects [94]. Beca et al. has demonstrated that PDE3A regulates basal myocardial contractility through collaborating with sarcoplasmic reticulum calcium ATPase type 2a signaling complexes in the heart of a mouse [95]. In spite of their vasodilatory and positive inotropic effects on the heart, Netherton et al. has shown that PDE3 inhibitors additionally dilate blood vessels in vivo, inhibit VSMC proliferation in vitro, relax isolated arterial and venous tissues, and limit aggregation of neointimal VSMC in arteries after in vivo vascular damage [96,97]. Movsesian et al. has shown that PDE3 inhibitors can be utilized as therapeutic agents for the treatment of

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ischemic and idiopathic expanded cardiomyopathy, a disorder portrayed by debilitated myocardial contractibility and improper pulmonary vasoconstriction [3]. Takahashi et al. has shown improved activities and gene expression of PDE types 3 and 4 in pressure-initiated congestive heart failure (CHF). During this animal model study, gene expressions of PDE3 and PDE4 were augmented from the hypertrophic stage. PDE3 and PDE4 activities are in this way enhanced in the CHF stage and seem to contribute to the development and exacerbation of CHF [98]. Molenaar et al. in their clinical trial has shown that PDE3, not PDE4, diminishes b1and b2-adrenoceptor-mediated inotropic and lusitropic effects in the failing ventricle in patients treated with metoprolol. The PDE3 blocker and metoprolol co-administration could conceivably facilitate cardio-stimulation evoked by vasoconstrictor through b2 adrenoceptors [99]. Hentschel et al. has shown that inhalation of the PDE3 inhibitor milrinone attenuates PHT in a rat model of CHF. Intravenous infusion of milrinone reduces both pulmonary and systemic arterial blood pressure. In contrast, inhalation of milrinone predominantly dilates pulmonary blood vessels, resulting in a reduced pulmonary-to-systemic vascular resistance ratio. Moreover, lung edema is significantly reduced by repeated milrinone inhalation [100]. Heart protection of PDE3A1 inhibitors against ischemiareperfusion injury is negatively regulated by b-AR signaling and inhibits cardiomyocyte apoptosis [101]. Moreover, Siriporn et al. has shown that cilostazol preserves cardiac mitochondrial function exposure to oxidative stress via preventing mitochondrial depolarization, mitochondrial swelling, and decreasing ROS production in the heart [102]. Nakano et al. analyzed the myocardial response to milrinone, a typical PDE3 inhibitor in single right ventricle (SRV) heart disease. The cAMP levels, PDE activity, and phosphorylated phospholamban (PLN) were determined in explanted human ventricular myocardium from non-failing pediatric donors and pediatric patients transplanted secondary to SRV. They have found that clinically, milrinone is experimentally begun in both types of subjects with SRV. They have concluded the molecular adaptation associated with SRV varies essentially from that which is exhibited in pediatric HF because of dilated cardiomyopathy. These modifications support a pathophysiologically distinct mechanism of HF in pediatric patients with SRV, which has guideline suggestions in regards to the assumed response to PDE3 inhibitor treatment in this population [89]. The PDE3A may play a critical role in cardiomyocytes survival. It has been shown down-regulation of PDE3A expression induces cardiomyocyte apoptosis in the cultured cardiomyocytes. Induction of apoptosis due to PDE3A down-regulation mediated by induction of the pro-apoptotic transcriptional repressor Inducible cAMP early repressors (ICER). However, the relevance of this finding with the side effect of long term administration of selective PDE3 inhibitors is clear. Ding et al. has found that the expression of cAMP hydrolyzing PDE3A is essentially diminished in human coming up hearts, accompanied by the up-regulation of ICER expression. The finding that PDE3 inhibitors induce an autoadministrative positive PDE3A–ICER feedback loop prompting cardiomyocyte apoptosis may offer a molecular mechanism in any event for the adverse effects of chronic PDE3 inhibitor therapy. The development of therapeutic strategies that intervene in the PDE3A–ICER feedback loop may be taken into account, advancing the gainful effects while preventing the detrimental effects of PDE3 inhibitor therapy [78]. We have found that selective PDE3 inhibitors produce an apoptotic effects higher than non-selective PDEs (unpublished data). By putting together all that information we may conclude that in cardiomyocyte, there are two cAMP pools with a different effect on cell proliferation and one of them is regulated by PDE3.

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4.4. PDE4 4.4.1. Overview Type 4 cyclic nucleotide PDE4 are a group of low km cAMPspecific PDE including at least 20 isozymes encoded by four genes (4A, 4B, 4C, and 4D) in mammals. PDE4B and PDE4D varieties are expressed in murine, rodent, and human cardiomyocytes, and specific PDE4 inhibitors have been proposed to have minor effects on Ca2+ currents and contractility [103–105]. PDE4 inhibitors include AN2728 and E6005 (topical ointments), apremilast, benafentrine, cilomilast, crisaborole, enoximone, ibudilast, luteolin, mesembrenone, mesembrine, rolipram (nanomolar), piclamilast, roflumilast, tibenelast, tetomilast, benafentrine, zardaverine, and tolafentrine that inhibits both PDE3 and PDE4. PDE4 is the standard cAMP hydrolyzing enzyme found in cells of the immune system, keratinocytes brain, smooth muscles, cardiovascular tissues, and inflammatory cells [106]. In the immune system, PDE4 inhibitors bring about the suppression of both T helper 1 (Th1) and T helper 2 (Th2) immune reactions [107]. Because of these immune modulating effects, PDE4 inhibitors are currently under scrutiny for an assortment of conditions including asthma, chronic obstructive pulmonary disease, atopic dermatitis, psoriasis, and psoriatic joint pain [108,109]. Moreover, the reviews have shown that PDE4 inhibitors are known to possess long-term memory-enhancing and pro-cognitive actions [110]. 4.4.2. Cardio-protection effects It has been suggested that PDE4 inhibitors, which have potential therapeutic use in treating sepsis, improve cardiac contractility in endotoxemia and it has been proposed that they may have an imperative role in treating critically ill patients [111]. Lin et al. has indicated PDE4 inhibition attenuates atrial natriuretic peptide-induced vascular hyper permeability and loss of plasma volume [112]. No studies have addressed whether the PDE4 expression profile is changed in HF. Given the particular spatial and temporal regulation of cAMP levels managed by distinct PDE4 subtypes, their adjusted expression in coronary illness would be anticipated to modify cardiovascular function. Enoxamone (PDE4 and possibly PDE3 inhibitor), a substituted imidazolone derivative, is an active inotropic agent. Despite initial promise, enoximone has neglected to demonstrate noteworthy advantages in patients with chronic severe HF in phase 3 clinical trials. Be that as it may, Lehnart et al. has shown that PDE4D deficiency in the ryanodine-receptor complex promotes HF and arrhythmias [113]. The small heat shock protein HSP20 is known to be cardio-protective during times of stress and the mechanism underlying its protective abilities depends on its phosphorylation on Ser16 by PKA. Sin et al. has shown that the disruption of the cAMP PDE4-HSP20 complex constricts the b-agonist induced hypertrophic response in cardiac myocytes [114]. Furthermore, Lourenco et al. has shown that increasing synaptic noradrenaline, serotonin, and histamine enhance in vivo binding of rolipram, a selective PDE4 inhibitor in the brain, lung, and heart of rats [115]. Visser et al. in their review have assessed PDE4 inhibition with piclamilast on normal lung development and its helpful effect on PHT and RVH in newborn rats with hyperoxia-induced lung injury; a useful study for premature infants with severe bronchopulmonary dysplasia. Treatment with piclamilast in both models attenuated RVH, reduced arteriolar wall thickness, and improved right ventricular function in the injury recovery model, but did not restore alveolarization or angiogenesis [116]. PI3K modulates myocardial contractility via a cAMP-dependent mechanism through the regulation of the catalytic activity of PDE4. Moreover, basal agonist-independent activity of the b2-AR and consequently cAMP production and improvement of the catalytic

activity of PDE4 through PI3K represents an example of integrative cellular signaling, which controls cAMP dynamics and in this way contractility in the cardiac myocyte. A review has shown that b2-adrenergic receptor-coupled PI3K constrains cAMP-dependent increases in cardiac inotropy through PDE4 activation [117]. Another review has shown that b-Adrenergic receptor stimulation expands surface Na-K-Cl co-transporter (NKCC2) expression in rat thick ascending limbs in a process inhibited by PDE4 [118]. In a mice model study, PDE4B regulates the Ca2+ current and ensures against ventricular arrhythmias in the cardiac L-type Ca2+ channel complex [119]. A study has shown that PDE4 activation by UCR1C (a novel activator of PDE4) attenuates cardiomyocyte hypertrophy by particularly repressing nuclear PKA activity [120]. 4.5. PDE5 4.5.1. Overview The cGMP-specific PDE5 is expressed in different tissues and functionally regulates cGMP-dependent signaling in aortic smooth muscle cells, heart, placenta, skeletal muscle, pancreas, and, to a substantially lesser extent, in the brain, liver, and lungs, but most conspicuously the corpus cavernosum and the retina. Sildenafil, vardenafil, avanafil, iodenafil, mirodenafil, udenafil, icariin, benzamidenafil, dasantafil, and tadalafil are PDE5 inhibitors that are fundamentally stronger and more specialized than zaprinast and other early PDE5 inhibitors [121]. 4.5.2. Cardio-protection effects PDE5 has been recently found to assume a key part in the cardiovascular system. In an assortment of chronic CVD, cGMP increases much of the time in view of maintained initiation natriuretic peptides, and it has been confirmed that PDE5 upregulation also happens; maybe as a countering mechanism. Expanded levels may identify with cGMP/PKG effects on transcription and posttranslational initiation. Upregulation has been represented in pneumonic hypertension, CHF, and RVH. Angiotensin II (AII) stimulation of VSMCs responds with rapid induction of PDE5A, which expands the AII reaction by diminishing cGMP/PKG signaling. This may expand hypertension and vascular proliferation in diseases involving renin/angiotensin stimulation. PDE5 additionally increments in the vascular rings and the venous circulation of rats, who are frequently administered nitroglycerin, which indicates a part in nitrate tolerance. Inhibition of PDE5 reverses this tolerance in effected vessels [122]. PDE5 metabolizes the NO and natriuretic peptide systems’ second messenger cGMP and along these lines may bind worthwhile NO and natriuretic peptide actions in the heart, vasculature, and kidney. Preclinical reviews suggest that inhibition of PDE5 reverses adverse cardiac structural and functional remodeling and enhances vascular, neuroendocrine, and renal function. In clinical studies, PDE5 inhibitor treatment enhances exercise tolerance and clinical status in patients with idiopathic PAH and in patients with HF and reduced ejection fraction [123]. A small, single center study of HF with preserved ejection fraction (HFpEF) has been observed to improve hemodynamics, left ventricular diastolic function, right ventricular systolic function, left ventricular hypertrophy, and lung function with 6 to 12 months of therapy with a PDE5 inhibitor compared with a placebo. In total, these reviews indicate the potential for PDE5 inhibition to ameliorate several key pathophysiological perturbations in HFpEF, and therefore enhance exercise capacity and clinical status [124]. Furthermore, an in vivo study has shown that sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity in mice [122]. It has been suggested that the beneficial effect of PDE5 inhibition

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on doxorubicin-induced HF is exerted via attenuating PKGia oxidation [125]. Isidori et al. has shown that in adult mice, selective PDE5 inhibition lowers contraction rate stimulated by b2AR, but not b1AR activation, supporting a compartmentalization of the cGMPmodulated pool of cAMP. They have concluded that inhibition of PDE5 counteracts b2-adrenergic signaling in beating cardiomyocytes [126]. However, Sugiyama et al. has detailed an inhibitory effect of sildenafil on the cAMP-hydrolyzing activity of canine and bovine cardiac ventricular membrane preparations. This controversy may indicate subcellular localization of PDE isoenzyme variety in species, and support the concept that the effects of selective PDE inhibitors are species-dependent [127]. A study has shown that sildenafil enhances endotheliumdependent flow-mediated vasodilation in patients with chronic HF [128]. Some studies have guaranteed that PDE5 restraint by

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sildenafil viably ensures against unfavorable left ventricular remodeling by focusing inhibition of hypertrophic and pro-fibrotic stimuli and modulation of cardiomyocyte stiffness [129]. In addition, tadalafil, a PDE5 inhibitor, protects against myocardial ischemia/reperfusion through the PKG-dependent generation of hydrogen sulfide mechanism [130]. Tadalafil also attenuates oxidative stress and protects against myocardial ischemia/reperfusion injury in type 2 diabetic mice [131]. Moreover, enhanced NO production is known to initiate SIRT1, which is a histone deacetylase that regulates the PGC-1a, a regulator of mitochondrial biogenesis and co-activator of transcription factors affecting vitality homeostasis. So, chronic treatment with tadalafil activates NO-induced SIRT1-PGC-1a signaling and attenuates mitochondrial dysfunction in type 2 diabetic hearts [132].

Table 2 The mechanisms of PDE5 inhibition in CVD. PDE inhibitor- CVD

Mechanism (s)

Study

1) Reducing oxidative stress (reduced levels of oxidative stress biomarkers, such as 8-iso-prostaglandin-F2a In vivo and 3-nitrotyrosine, and significantly increased NO levels). 2) Suppressed proliferation and enhanced apoptosis of pulmonary artery smooth muscle cells, attenuating small pulmonary artery remodeling, and RVH. 3) Reduced pulmonary vascular resistance and increased cardiac output 4) Increased endothelial NO synthase expression and superoxide dismutase (SOD) activity, and downregulated nicotinamide adenine dinucleotide phosphate oxidase expression Decrease in pulmonary vascular resistance, mean pulmonary artery pressure and an increase in Fick cardiac In vivo1 PDE5 inhibitor-Porto-PHT output. Limited endothelin-1 production in the endothelium of small coronary arteries In vivo & in EMD360527-CV vitro In vivo 1) Produced coronary resistance vessel dilation EMD-360527-MI 2) Reduced in coronary resistance vessels 3) Attenuation of coronary vasodilation Attenuating apoptosis and regulating microRNAs expression In vivo Sildenafil-PIMD LASSBio-1386-PHT Prevention right ventricular dysfunction and exercise intolerance In vivo Tadalafil-HF 1) Attenuated the increase in cardiac hypertrophy and pulmonary edema following infarction In vivo 2) Reduced ejection fraction and preserves left ventricular function Anti-remodeling effect, resulting in improved cardiac kinetics and circulating markers exerted through a direct Clinical 2 Sildenafil-Cardiac myopathy intra-myocardial action 1) Improvements in pulmonary and systemic hemodynamics resulting in biventricular unloading Clinical 2 Sildenafil-Aortic stenosis 2) Reduced systemic and pulmonary vascular resistance, mean pulmonary artery and wedge pressures, and increased systemic and pulmonary vascular compliance and stroke volume index 3) Caused a modest decrease in mean systemic arterial pressure Increases the success of resuscitation through improving macro-circulation and microcirculation during VF In vivo Sildenafil-VF and Cardiopulmonary resuscitation Improves arterial stiffness and reducing pulse wave velocity after exercise but not exercise capacity Clinical 2 Sildenafil-HTN Tadalafil-PAH Induced pulmonary arterial relaxation (while oral administration of tadalafil decreased pulmonary arterial In vivo pressure) Decreased right ventricular systolic pressure, right ventricular weight, pulmonary vascular remodeling and a In vivo Vardenafil-PHT significant better exercise capacity In vivo Vardenafil-Vascular 1) Improved endothelial function 2) Slight sensitization of vascular smooth muscle to NO dysfunction Prevented the development of right ventricular systolic pressure, and RVH In vivo Tadalafil-PHT Sildenafil-Tadalafil- Refractory 1) Improvement in hemodynamic parameters and exercise tolerance Clinical 3 PAH 2) Decrease in mean pulmonary arterial pressure and pulmonary vascular resistance 3) Increase in cardiac index and 6-min walk test Tadalafil-PHT Prevented hypoxia-induced oxidative stress In vivo Sildenafil- Ischemic In vivo 1) Improved ventricular recovery, a reduced incidence of ventricular fibrillation and decreased myocardial myocardium infarction 2) At higher doses increase in the incidence of ventricular fibrillation while at very low doses it had no effect on cardiac function Sildenafil- Cardiac hypertrophy 1) Suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to In vivo chronic pressure overload induced by transverse aortic constriction 2) Reverses pre-established hypertrophy induced by pressure load while restoring chamber function to normal 3) Deactivates multiple hypertrophy signaling pathways triggered by pressure load (the calcineurin/NFAT, phosphoinositide-3 kinase (PI3 K)/Akt, and ERK1/2 signaling pathways) In vivo Vaso-relaxant activity on pulmonary arteries Curcumin analogues (new PDE5 inhibitor)- PAH Vardenafil-PAH

Abbreviations: CVD; cardiovascular disease, PAH; pulmonary arterial hypertension, VF; Ventricular fibrillation, PHT; Pulmonary hypertension, myocardial and intestinal microcirculatory dysfunction, CV; Coronary vasoconstriction, HTN; hypertension. 1 Single-center retrospective cohort study. 2 Randomized, placebo-controlled study. 3 Retrospective study.

Reference [150]

[151] [152] [153]

[154] [155] [156] [157] [158]

[159] [160] [161] [162] [163] [164] [165]

[166] [167]

[168]

[169]

PIMD; Post-resuscitation

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Pokreisz et al. has shown that ventricular PDE5 expression is expanded in patients with advanced HF and subsequently contributes to adverse ventricular remodeling after myocardial localized necrosis in mice [133]. A similar study has shown that PDE5 is profoundly expressed in the hypertrophied human right ventricle, and acute inhibition of PDE5 increases right ventricular inotropy and decreases right ventricular afterload without significantly affecting systemic hemodynamics; thus, enhancing contractility, particularly PAH [134]. Although PDE5 inhibition by sildenafil failed to prevent or reverse RVH in rats operated on by pulmonary trunk banding, it increased RVH and improved right ventricular contractile function when given to rats with established RVH [135]. Likewise, Senzaki et al. [124] reported confirmation for PDE5A expression in canine cardiomyocytes, which is still disputable regarding human cardiomyocytes. A study has shown that utilizing vardenafil in rats with type 2 diabetes prevents the development of HF with preserved ejection fraction [136]. Recently, a lower limit for ventricular tachycardias was indicated in a pacing model of isolated swine right ventricles treated with a high dose of sildenafil consolidated with a NO donor [137]. Furthermore, the natriuretic peptide pathway influences the response to PDE5 inhibition in hypoxia-induced PHT, particularly its consequences on RVH and vascular remodeling in mice [138]. The PDE5 action in systemic and pulmonary vasculature increments in HF renders hemodynamic reactions to PDE5 inhibition indistinguishable to those from B-type natriuretic peptide (BNP) infusion. Forfia et al. has shown that acute PDE5 inhibition mimics the hemodynamic effects of BNP and potentiates BNP effects in failing, but not in the normal canine heart [139]. Right ventricular function immediately after left ventricular assist device (LVAD) implantation is a critical prognostic factor. In a review, Hamdan et al. prevented right HF after LVAD implantation by sildenafil [140]. Modulation of the NO-sGC-cGMP pathway by sildenafil or sGC stimulator riociguat facilitates beneficial results on pulmonary hemodynamics and right ventricular function in the experimental model of secondary PHT due to left heart disease. In this manner, riociguat and sildenafil ameliorate PHT due to left heart disease in mice [141]. A case-control study has shown that in patients with advanced HF and severe PHT, sildenafil therapy has beneficial effects on hemodynamics, clinical status, cardiovascular cachexia, and contributes to enhanced peri-transplant survival [142]. Diastolic Ca2+ waves in heart myocytes prompt arrhythmias by initiating postponed after-depolarizations. Sildenafil smothers waves prompted by hoisted outer Ca2+ by means of a PKG mechanism. This concealment is interceded by decreased SR content, which itself is brought about by lessened sarco-(endo)-plasmic reticulum Ca2+-ATPase (SERCA) capacity and conceivable diminished ICa-L [143]. PDE5 inhibitor increases SERCA activity via phosphorylation of PLN at Ser16. This may contribute to the attenuation of endoplasmic reticulum (ER) stress induced by PDE5 inhibition. Gong et al. has shown that chronic inhibition of cGMP-specific PDE5 can attenuate ER stress and improve cardiovascular function in HF [144]. Volume-overloaded hearts appear to under-express PDE5 and have an attenuated contractile response to b-adrenergic stimulation. This study proposes that b-adrenergic agents and PDE5 inhibitors may be less effective in treating right HF resulting from right ventricular volume overload [145]. Gong et al. has shown that in isolated cardiac fibroblasts, sildenafil blocked transforming growth factor (TGF)-b1-induced cardiac fibroblast transformation, proliferation, and collagen synthesis. Furthermore, they found that sildenafil induced phosphorylated cAMP response to element binding protein (CREB) and reduced CREB-binding protein 1 (CBP1) recruitment to Smad transcriptional complexes. Thus, they have concluded that chronic

inhibition of cGMP-specific PDE5 prevents cardiac fibrosis through inhibition of TGF-b-induced Smad signaling [146]. In addition, concomitant PDE5 inhibition enhances myocardial protection by inhaled NO in ischemia-reperfusion injury [147]. In a meta-analysis of 1622 treated subjects, it has been suggested that PDE5 inhibition has anti-remodeling properties and improves cardiac inotropism, independently of afterload changes, with a good safety profile. Given the reproducibility of the findings and tolerability across different populations, PDE5 inhibitor could be reasonably offered to males with cardiac hypertrophy and early stage HF. However, considering the limited gender data, a larger trial on the sex-specific response to long-term PDE5 inhibitor treatment is required for proof of concept [148]. Thieme et al. has shown that PDE5 seems to be the predominant PDE, regulating renal blood flow and renal vascular function. Additionally, sildenafil ameliorates Ang II-dependent hypertension and improves vascular dysfunction. No effect of PDE5 inhibition was seen in eNOS-knockout mice supporting the hypothesis that Ang II initiates PDE5 at first by expanded NO/cGMP generation [149]. The other mechanisms of PDE5 inhibition are shown below (Table 2). 4.6. PDE6 4.6.1. Overview PDE6 (also called photoreceptor specific PDE) is the essential controller of cytoplasmic cGMP concentration in rod and cone cells and selectively inhibited by dipyridamole, vardenafil, tadalafil, and zaprinast. After activation by rhodopsin, the GDP transduces, the Ga subunit of the hetero-trimer G-protein of the hetero-trimer, which is exchanged for GTP and the Gat-GTP diffuses and binds to a membrane-associated photoreceptor specific cGMP-PDE (PDE6) decreasing cell cGMP levels as the second messenger of light signal transduction system. 4.6.2. Cardio-protection effects Selective PDE6 inhibitors are few and have little applications because of adverse effects on the vision specific localization of PDE6. Most PDE5-selective inhibitors act as excellent PDE6 inhibitors, but bibliographical data about the representatives of this group is sparse. Although recently, PDE6 has taken on another utilitarian part, in which chick pineal gland cells, rod and cone forms of PDE6 are expressed and assume a part in the inhibition by light of melatonin synthesis [5,170,171]. 4.7. PDE7 4.7.1. Overview The PDE7 family is composed of two genes: PDE7A and PDE7B. High mRNA concentrations of both PDE7A and PDE7B are expressed in the rat brain (cerebellum, dentate gyrus of the hippocampus, and striatum) and in numerous peripheral tissues; however, the appropriation of these enzymes at the protein levels has not been reported. PDE7B mRNA was plentifully expressed in the brain and heart, followed by the skeletal muscle and pancreas [172,173]. Notwithstanding, selective PDE7 inhibitors are few and have little applications. The PDE7 inhibitors include ASB16165, IR202, US8637528, IR-284, and BRL-50481. 4.7.2. Cardio-protection effects Beginning proof has shown that PDE7 has an important role in the activation of T-cells. However, results based on the use of PDE7A knockout mice (PDE7A-/-) has failed to confirm the role of PDE7A in T-cell proliferation and has suggested that this PDE could have some other role in the control of humoral immune responses.

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PDE7A expressed in human B-lymphocytes is up-regulated by CaM [174]. Thus, selective PDE7A inhibitors could explain the capability of PDE7A in regulating cGMP-dependent signaling and as a pharmacological target in the context of the immune and neurological responses. PDE7A1 protein is most noticeable in T-cell lines, peripheral blood T-lymphocytes, airway and vascular smooth muscle cells, lung fibroblasts, epithelial cell lines, and eosinophils; however, it was not identified in neutrophils. Interestingly, the PDE7A2 protein, identified in human cardiac myocytes, was not found in any of the other investigated cell types. 4.8. PDE8 4.8.1. Overview The PDE8 family particularly hydrolyses cAMP has the highest affinity for cAMP among all the PDEs and is insensitive to rolipram, IBMX and cGMP [175]. Two PDE8 genes (PDE8A and 8B) have been identified and PDE8A mRNA has the highest expression in testis, followed by the eye, liver, skeletal muscle, heart, kidney, ovary and brain, in decreasing order. One to five splice variants of PDE8 were cloned from testis and T cells [176] and five variants of PDE8B have been identified [177]. RT-PCR studies have shown that PDE8B1 is mostly present in the thyroid gland, PDE8B1 and PDE8B3 are equally expressed in the placenta, and PDE8B3 is the most rich form that is found in the brain [178]. 4.8.2. Cardio-protection effects Curiously, PDE8 adjusts excitation-contraction coupling in ventricular myocytes, revealing its participation in cardiac function [179]. PF-04957325, the recently produced selective PDE8 inhibitor [180] is helpful to concentrate the role of PDE8 in cardiovascular pathologies. A recent study with PDE8A knockout mice has shown that PDE8A is expressed in ventricular myocytes of mouse hearts. Myocytes from PDE8 knockout hearts elicit greater isoprenaline-induced increases in Ca2+ transients, L-type Ca2+ channel currents (ICa), and Ca2+ spark activity, suggesting that PDE8A controls cAMP involved in Ca2+ handling in cardiomyocytes. Interestingly, PDE8A deletion results in leaky ryanodine receptor (RyR) channels observed by a compensatory increase in SR Ca2+ refilling [179]. 4.9. PDE9 4.9.1. Overview The PDE9 family particularly hydrolyses cGMP has the highest affinity for cGMP amongst all PDE families and is insensitive up to 100 mM in most reference PDE inhibitors, notably in IBMX, although zaprinast inhibits PDE9 with an IC50 value of 35 mM [181]. More than 20 splice variants for PDE9 have been identified [182]. PDE9A6 is cytosolic, whereas PDE9A1 is associated with the nucleus [183]. PDE9 mRNA is detected in peripheral tissues including the kidney and several brain regions of both rat and human including the cortex, hippocampus, basal ganglia and cerebellum, where it is located predominantly but not exclusively within neurons [184]. BAY 73-6691 inhibits PDE9A with a 25-fold greater selectivity compared with all other PDEs [185]. The utilization of BAY 73-6691 in rodents has demonstrated that PDE9 inhibition increases learning and memory [186]. An orally bioavailable PDE9 inhibitor was synthetized for use as a potential hypoglycemic agent [187]. Lastly, PF-04447943, a brain penetrant PDE9A inhibitor that improves synaptic plasticity and cognitive function in rodents has been evaluated [184].

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4.10. Cardio-protection effects The cGMP-specific PDE9 was found to be expressed in rodent and human hearts, and to be upregulated in hypertrophy and HF [188]. PDE9 genetic removal or pharmacological inhibition seems to protect the heart against pathological remodeling during pressure overload. Moreover, PDE9 inhibition reverses pre-established heart disease in a NO synthase activity-independent manner, whereas PDE5 inhibition requires active NO synthase, which is decreased in HF. This is because PDE9 seems to hydrolyze cGMP specifically, which is generated by natriuretic peptides, whereas PDE5 controls cGMP generated by NO [189,190]. In addition, Lee et al. in their study showed that PDE9A can direct cGMP signaling independent of the NO pathway, and its part in stress-induced heart disease proposes it as a potentially helpful target [188]. 4.11. PDE10 4.11.1. Overview The PDE10 family encoded by the unique gene PDE10A, is a dual cAMP/cGMP PDE, and expressed at high levels in the striatal medium spiny neurons, but is expressed at very low levels elsewhere in the brain and other tissues [191]. PDE10 inhibition mimics D2 dopamine receptor antagonism in the indirect striatopallidal output pathway through expanding cAMP and cGMP levels. This antagonistic effect could increase the activity of the striatonigral output and normalize the reduced striatal output that characterizes schizophrenia [192]. Because of its kinetic properties for cAMP and cGMP hydrolysis, cGMP hydrolysis by PDE10 is powerfully restrained by cAMP, which is notably the opposite compared with the PDE3 family [13]. The first known potent and specific PDE10A inhibitor is papaverine, with an EC50 value of 36 nM [193]. Azetidine and piperidine compounds, Imidazo [1,2-b] pyridazine derivatives, Heteroaryloxycarbocyclyl compounds and Aryl- and heteroarylnitrogen-heterocyclic compounds are useful as PDE10 inhibitors. There are 18 splice variants for PDE10A [194]. PDE10A is expressed mainly in the brain particularly in striatal medium spiny neurons, in the pineal gland and, to a lower extent, in the testis. TP-10, a new potent and very specific PDE10 inhibitor synthesized by Pfizer, has been investigated in a preclinical study as a new therapeutic approach for the treatment of schizophrenia [195]. Recently, it has been shown that this PDE10 inhibitor has the ability to improve striatal and cortical pathology in a mouse model with Huntington’s disease [196], and that PDE10A plays a key role in the pathophysiology of Parkinson’s disease [197]. 4.11.2. Cardio-protection effects Intimal hyperplasia described by abnormal aggregation of smooth muscle cell (SMC) – like cells and inflammatory cells – is a sign of vascular occlusive issue, for example, post angioplasty restenosis, vein graft atherosclerosis, and allograft vasculopathy. PDE10A expression is especially elevated in the intimal SMC-like cells, macrophages in mouse models of vascular injury and in human atherosclerotic lesions. Studies suggest that PDE10A is important in pathological vascular remodeling in vivo. A recent study has shown that for the first time PDE10A has a central role in progressive pulmonary vascular remodeling and the study proposes a novel therapeutic approach for the treatment of PHT [198]. 4.12. PDE11 4.12.1. Overview The PDE11 family represents a dual-substrate PDE family having a catalytic site more similar to PDE5 than to PDE10A. PDE11

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Fig. 2. Proposed mechanisms of PDE inhibitors in CVD.

is mainly present in the prostate and to a lower extent in the pituitary gland, liver, and heart [199]. PDE11A is inhibited by dipyridamole (IC50 = 0.9–1.8 mM), zaprinast (IC50 = 5–33 mM), IBMX (IC50 = 25–81 mM), and is insensitive to EHNA, rolipram, and milrinone. There is no selective inhibitor for PDE11A; however, amongst the newly launched PDE5 inhibitors, tadalafil was the

most potent (IC50 = 37–73 nM), inhibiting both cAMP and cGMP hydrolysis [200,201]. 4.12.2. Cardio-protection effects In spite of the fact that PDE11A is expressed in very restricted brain regions, such as the ventral hippocampus, its deletion in a

Fig. 3. The clinical utilities of PDE inhibitors in CVD.

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551

Table 3 Plants and active constituents with selective PDE inhibition activity. Number

Plant

Family

Part of plant/Active constituent

Inhibitory Effect

Reference

1 2 3 4 5 6 7

Periandra dulcis Mart Daidzein Genista tinctoria (Genistein) Vitis vinifera Curcuma longa (Curcumin) Citrus-Fruits Rhamnus nakaharai

Leguminosae – Fabaceae Vitaceae Zingiberaceae Rutaceae Rhamnaceae

Roots/Saponins Grape skin/Anthocyanin Fruit/Flavonoid Stem bark/Quercetin

PDE1I PDE3I PDE4I PDE5I PDE5I PDE1, 4, 5I Selective and competitive PDE3I and PDE4I

[212] [213] [213] [214] [169] [215] [216]

knockout mouse model caused psychiatric disease-related phenotypes [202]. Carney complex patients possess PDE11A variants with a high frequency, suggesting that PDE11A is a genetic factor for the development of testicular and adrenal tumors [203]. The search for selective PDE family inhibitors might benefit from the use of yeast-based assays, which have been reported to be useful for detecting and characterizing inhibitors of either cAMPor cGMP-metabolizing PDEs [204]. Proposed mechanisms of PDE

inhibitors and their clinical utilities in CVD are shown in Figs. 2 and 3, respectively. 5. Natural PDE inhibitors In the recent decade, natural medicines have become of interest worldwide, and this enthusiasm for plant-based medications is increasing [205–208]. Albeit current medications might be accessible worldwide, herbal medicines have maintained their

Table 4 Plants and active constituents with non-selective PDE inhibition activity. Number

Plant

Family

Part of plant/Active constituent

Inhibitory Effect

Reference

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

Crataegus oxyacantha Decussocarpus rospigliosii Plantago species Scutellaria baicalensis Anemarrhena asphodeloides Iris florentina Polygala tenuifolia Glycyrrhiza glabra var. gkzndulifera Nepeta japonica Cassia obtusifolia Daphne genkwa Carthamus tinctorius Bupleurum facatum Asiasarum sieboldi Zanthoxylum piperitum Fraxinus bungeann Citrus reticulate Nuphar japonicum Inula britannica Amomum costatum Areca catechu Aralia elata Phyllostachys nagra Anemarrhena asphodeloides Caesalpinia sappan Forsythia suspensa Ginkgo biloba Eucommia ulmoides Viscum album Eleutherococcus senticosus Forsythia suspensa Papaver somniferum (Papaverine) Amorpha Fruticosa (Amorphin) Kaempferol Quercetin Picrasma quassioides Ailanthus altissima Simaba cuspidata Murraya paniculata Hibiscus mutabilis Scutellaria rivularis Helenium autumnale Daphne genkwa

Rosaceae Podocarpaceae Plantaginaceae Lamiaceae Asparagaceae Iridaceae Polygalaceae Fabaceae Lamiaceae Fabaceae Thymelaeaceae Asteraceae Apiaceae Aristolochiaceae Rutaceae Oleaceae Rutaceae Nelumbiaceae Asteraceae Zingiberaceae Arecaceae Araliaceae Poaceae Agavaceae Fabaceae Oleaceae Ginkgoaceae Ecommiaceae Viscaceae Araliacea Oleaceae Papaveraceae Fabaceae

Leaves and flower/Flavonoid Leaves/Flavonoid -/Plantaginin -/Flavanone Rhizome/Norlignan Rhizome/Norlignan Radix/Norlignan Radix/Norlignan Whole plant/Norlignan Whole plant/Norlignan Flower-bud/Norlignan Flower/Norlignan Radix/Norlignan Radix/Norlignan Fruit/Norlignan Bulk/Norlignan Peel/Norlignan Radix/Norlignan Flower/Norlignan Fruit/Norlignan Peel/Norlignan Root/Norlignan Cortex/Norlignan Rhizome/Norlignan Wood/Norlignan Fruit/Norlignan Leaves/Flavonoid Bark/Lignans Stem/Viscolin -/Glucoside Fruit/Norlignan -/Papaverine -/Amorphin

PDEI PDEI cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP PDEI cAMP cAMP cAMP PDEI PDEI

[217] [218] [219] [220] [221] [221] [221] [221] [221] [221] [221] [221] [221] [221] [221] [221] [221] [221] [221] [221] [221] [221] [221] [221] [221] [221] [222] [223] [224] [219] [219] [225] [226]

– – Simaroubaceae Simaroubaceae Simaroubaceae Rutaceae Malvaceae Lamiaceae Asteraceae Thymelaeaceae

-/Alkaloid -/Alkaloid -/Quassinoids Flower/Flavonoid Flower/Flavonoid -/Flavonoid -/Flavonoid Flower-bud/Norlignan

cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP cAMP

34 35 36 37 38 39 40 41 42 43

PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI

PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI PDEI

[227] [227] [228] [228] [228] [220] [220] [220] [220] [220]

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prevalence for historical and cultural reasons. Currently, many individuals in developed countries have started to show an interest to complementary therapies, including medicinal herbs such as PDE inhibitors [209–211]. Plants and active constituents with PDE inhibition activity are shown in Tables 3 and 4. 6. Concluding remarks The design of novel synthetic or natural selective inhibitors is progressively determined by better understanding the biology of PDEs and PDE inhibitors. In the cardiac myocyte, PDEs, which control cAMP and cGMP, are crucial in the regulation of a variety of biological functions, including pace-making, contractility, cell growth, and survival. The studies mentioned have yielded information about the unique potential roles of PDE inhibitors in CVD. As we improve our understanding of the physiological roles of the individual PDE isoforms parallel with the development of even more selective inhibitors of these chemicals, it is likely that better therapeutically active drugs will emerge. Finally, the role of PDE inhibitors in CVD and heart function also merit further research, and could have considerable therapeutic potential in the treatment of various diseases. Conflict of interests The authors confirm that there are no conflicts of interests. References [1] D. Kessing, J. Denollet, J. Widdershoven, N. Kupper, Self-care and all-cause mortality in patients with chronic heart failure, JACC: Heart Fail. 4 (3) (2016) 176–183. [2] F. Vakilian, A.A. Rafighdoost, A.H. Rafighdoost, A. Amin, M. Salehi, Liver enzymes and uric acid in acute heart failure, Res. Cardiovasc. Med. 4 (4) (2015). [3] M.A. Movsesian, R. Alharethi, Inhibitors of cyclic nucleotide phosphodiesterase PDE3 as adjunct therapy for dilated cardiomyopathy, Expert Opin. Investig. Drugs 11 (11) (2002) 1529–1536. [4] A.M. Sharifi, S.H. Mousavi, B. Larijani, Study of interaction between nitric oxide and ACE activity in STZ-induced diabetic rats: role of insulin, Pharmacol. Res. 50 (3) (2004) 261–266. [5] R. Ghosh, O. Sawant, P. Ganpathy, S. Pitre, V. Kadam, Phosphodiesterase inhibitors: their role and implications, Int. J. PharmTech Res. 1 (4) (2009) 1148–1160. [6] A. Das, D. Durrant, F.N. Salloum, L. Xi, R.C. Kukreja, PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer, Pharmacol. Ther. 147 (2015) 12–21. [7] M. Conti, J. Beavo, Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling, Annu. Rev. Biochem. 76 (2007) 481–511. [8] T. Keravis, C. Lugnier, Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments, Br. J. Pharmacol. 165 (5) (2012) 1288–1305. [9] M. El-Metwally, R. Shafiee-Nick, N.J. Pyne, B.L. Furman, The effect of selective phosphodiesterase inhibitors on plasma insulin concentrations and insulin secretion in vitro in the rat, Eur. J. Pharmacol. 324 (2) (1997) 227–232. [10] K. McCormick, G.S. Baillie, Compartmentalisation of second messenger signalling pathways, Curr. Opin. Genet. Dev. 27 (2014) 20–25. [11] M. Golkowski, M. Shimizu-Albergine, H.W. Suh, J.A. Beavo, S.-E. Ong, Studying mechanisms of cAMP and cyclic nucleotide phosphodiesterase signaling in Leydig cell function with phosphoproteomics, Cell. Signal. 28 (7) (2015) 764– 778. [12] D.H. Maurice, H. Ke, F. Ahmad, Y. Wang, J. Chung, V.C. Manganiello, Advances in targeting cyclic nucleotide phosphodiesterases, Nature reviews, Drug Discov. 13 (4) (2014) 290. [13] A.T. Bender, J.A. Beavo, Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use, Pharmacol. Rev. 58 (3) (2006) 488–520. [14] S.H. Francis, M.A. Blount, J.D. Corbin, Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions, Physiol. Rev. 91 (2) (2011) 651–690. [15] C. Mehats, C.B. Andersen, M. Filopanti, S.C. Jin, M. Conti, Cyclic nucleotide phosphodiesterases and their role in endocrine cell signaling, TRENDS Endocrinol. Metab. 13 (1) (2002) 29–35. [16] T.J. Torphy, B.J. Undem, Phosphodiesterase inhibitors: new opportunities for the treatment of asthma, Thorax 46 (7) (1991) 512–523.

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