Unknown face of known drugs – what else can we expect from angiotensin converting enzyme inhibitors?

Author’s Accepted Manuscript Unknown face of known drugs – what else can we expect from angiotensin converting enzyme inhibitors? Anna Wzgarda, Robert Kleszcz, Monika Prokop, Katarzyna Regulska, Milosz Regulski, Jaroslaw Paluszczak, Beata J. Stanisz www.elsevier.com/locate/ejphar

PII: DOI: Reference:

S0014-2999(16)30811-1 http://dx.doi.org/10.1016/j.ejphar.2016.12.031 EJP70993

To appear in: European Journal of Pharmacology Received date: 30 October 2016 Revised date: 14 December 2016 Accepted date: 20 December 2016 Cite this article as: Anna Wzgarda, Robert Kleszcz, Monika Prokop, Katarzyna Regulska, Milosz Regulski, Jaroslaw Paluszczak and Beata J. Stanisz, Unknown face of known drugs – what else can we expect from angiotensin converting enzyme inhibitors?, European Journal of Pharmacology, http://dx.doi.org/10.1016/j.ejphar.2016.12.031 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Unknown face of known drugs – what else can we expect from angiotensin converting enzyme inhibitors? Anna Wzgarda1*, Robert Kleszcz2, Monika Prokop3, Katarzyna Regulska4, Milosz Regulski5, Jaroslaw Paluszczak2, Beata J. Stanisz1 1

Chair and Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, ul. Grunwaldzka 6, 60-780 Poznan, Poland;

2

Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, ul. Swiecickiego 4, 60-781, Poznan Poland;

3

Department of Endocrinology and Diabetology, Children's Memorial Health Institute, al. Dzieci Polskich 20, 04-730 Warsaw, Poland;

4

Greater Poland Oncology Center, ul. Garbary 15, 61-866 Poznan, Poland;

5

Chair and Department of Toxicology, Poznan University of Medical Sciences, ul. Dojazd 30, 60631 Poznan, Poland;

*Corresponding author. Anna Wzgarda, e-mail: [email protected], Abstract The renin-angiotensin system (RAS) is one of important systems among homeostatic mechanisms that controls the function of cardiovascular, renal and adrenal systems. As RAS has a very complex nature, it has been also found as related to the control of cell migration and apoptosis. Angiotensin-converting enzyme inhibitors (ACEI) are drugs most commonly used in the modulation of RAS activity. ACEI have been extensively described as effective in the treatment of hypertension among adults, but also as drugs delaying progression in diabetic nephropathy and reducing mortality in left ventricular dysfunction and congestive heart failure. What is less obvious, ACEI are also widely used in pediatric nephrology and cardiology. Moreover, there are more and more reports showing evidence that ACEI can be beneficial in the treatment of many other diseases and the pleiotropic activity of ACEI is mainly based on their antioxidant properties. In this paper we focus on the less obvious possibilities of the clinical use of ACEI in neurological or oncological patients, discuss the role of ACE gene polymorphism and show the perspectives of potentially new applications of ACEI in contemporary 2

pharmacotherapy. Keywords: RAS, Angiotensin-converting enzyme inhibitors, pleiotropic activity

1. Introduction The renin-angiotensin system (RAS) is responsible for cardiovascular, renal and adrenal homeostasis and the physiological maintenance of blood pressure. The angiotensin-I converting enzyme (ACE) is a crucial enzymatic component of this system, and its main role is the convertion of angiotensin I (Ang I) to angiotensin II (Ang II) (Brown and Vaughan, 1998; Carey and Siragy, 2003; Paszun and Stanisz, 2008; Regulska et al., 2014; Sica, 2010; Thind, 1990). When RAS works deficiently and cannot regulate the balance between Ang I and Ang II, this reaction can be targeted by a well-known group of drugs - ACE inhibitors (ACEI). ACEI were developed as antihypertensive agents and the effects of ACEI on the RAS are well documented. However, there are more and more reports about numerous beneficial effects resulting from their pleiotropic activity which are clinically relevant. ACEI have been proven to be very efficient as cardioprotective and nephroprotective agents in various clinical trials, especially in patients with a high risk of cardiological events and comorbidities, and their pleiotropic activity can be seen beyond the circulatory system (Daly et al., 2005; George et al., 2010; Lever et al., 1998; Regulska et al., 2013; Stanisz et al., 2014; Wiggins et al., 2008; Zheng et al., 2009). For a complete understanding of their complex action the topic of genetic polymorphism must also be discussed (Fig. 1) (Sugimoto et al., 2006; Zha et al., 2015). Fig. 1.

2. Pediatrics 2.1. Can pediatric patients be treated with ACEI? ACEI are a group of pharmacological agents widely used in pediatric population. They are recommended in such conditions as hypertension, heart failure (in both the treatment and prevention, e.g. in Duchenne dystrophy) and renal diseases (among others in the nephrotic syndrome, hemolytic-uremic syndrome (HUS) and Alport syndrome). Drugs influencing the RAS, i.e. ACEI and angiotensin II type I receptor (AT1R) blockers (ARB) are always of first choice in the treatment of hypertension if there are such concomitant conditions as heart failure (HF), systolic dysfunction, coronary disease, proteinuria, chronic kidney disease or type 2 diabetes (Assadi, 2012). ACEI inhibit the conversion of Ang I to Ang II, which is a vasoconstrictor that also causes 3

aldosterone secretion. In addition, ACEI cause a decrease in bradykinin metabolism (Fig. 1), which is also thought to play a role in the anti-hypertensive effects of these medications. In children, due to the high prevalence of hypertension secondary to renal diseases, ACEI are a popular treatment choice. The benefit for patients with renal disease stems from the decrease in intraglomerular pressure caused by dilatation of the efferent arteriole, which leads to decreased filtration pressure and thus decreased proteinuria. This effect has been shown in children as well as in adults. Compared with other anti-hypertensive agents, there is the largest amount of evidence to support use of ACEI in the pediatric population (Mayers et al., 2011). 2.2. Heart failure Another aspect of the use of ACEI is concerned with the long-term treatment of HF. The use of ACEI therapy is indicated in children with HF caused by primary heart muscle disease of the systemic left ventricle. However, beneficial effects of such therapy have not been proven in patients with systemic right ventricle, for example in cases of transposition of the great arteries (Dore et al., 2005). Randomized trials in adult patients have repeatedly shown that at optimal dosages these drugs reduce symptoms and improve survival of patients suffering from HF. Studies in children have focused predominantly on hemodynamic markers. Some retrospective data have demonstrated a survival benefit for children with cardiomyopathy (CM) and HF (Stern et al., 1990), but yet other data have failed to show any survival benefit (Kantor et al., 2010; Burch et al., 1994). Although widely used, ACEI therapy remains invalidated by any randomized, controlled trial investigating survival in children with symptomatic HF (Kantor et al., 2013). 2.3. Duchenne’s muscular dystrophy Recent data suggests that the use of a tissue-specific ACEI (perindopril) in boys with Duchenne’s muscular dystrophy (DMD) can delay the progression of left ventricle (LV) remodeling. In DMD the absence of dystrophin in cardiac tissue leads to cardiomyocyte’s death and fibrosis with a clinical picture of CM and late HF. There is evidence for potential usefulness of long-term treatment with ACEI to reduce advanced fibrosis of dystrophic muscle in the mdx mouse model as well as for efficacy of early treatment with perindopril, which delays the onset and progression of prominent LV dysfunction in children with DMD (Cozzoli et al., 2011; Duboc et al., 2005). In an experimental model of dystrophin deficiency, the extent of sarcolemmal damage was directly related to the mechanical stress placed on the muscle. Hence the hypothesis that led to this clinical trial of perindopril: reduction of LV afterload (wall stress) should decrease the rate and extent of damage to the myocardium produced by contractions in the absence of dystrophin (Stephen, 2005). 4

In contrast, ACEI therapy has appeared to be only marginally effective in anthracycline-induced CM. A retrospective review of doxorubicin-exposed survivors of childhood cancer with HF revealed that treatment with enalapril was associated with only transient improvement in LV dimension, afterload, and systolic function (Armenian et al., 2012). 2.4. Renal disfunctions Moreover, ACEI are already well established reno-protective agents and it has been proven that enalapril is effective in reducing proteinuria in children with chronic kidney disease (Hari et al., 2013). In steroid-resistant nephrotic syndrome (SRNS) reducing proteinuria results in delayed deterioration of renal function and remission of proteinuria predicts a good long-term prognosis. The combination of highdose ARB and high-dose ACEI therapy is safe and effective in reducing proteinuria in childhood SRNS (Supavekin et al., 2012). The efficacy of the treatment with ACEI has been also investigated in children with Alport syndrome (AS), which is a hereditary renal disease characterized by persistent hematuria, proteinuria, and progressive renal failure. It has been proven that early and long-term ACEI and ARB treatment is efficient and well tolerated in children with AS. The anti-proteinuric effect of ACEI and ARB is of equal value in children with severe and less severe mutations in the COL4An gene, which is one of the mutations responsible for AS (Zhang et al., 2016). Moreover, several recent publications report on the anti-proteinuric effect of ACEI in post-diarrheal HUS in children in Argentina, where HUS is the second most prevalent cause of chronic renal failure (CRF). It has been shown that the administration of ACEI or ARB has a beneficial effect in children suffering from HUS without serious adverse events. Enalapril has two different effects on the kidney: first, which appears during early days after onset of treatment consisting of hemodynamic changes, and the antiproteinuric effect, which appears later. Also treatment with both ACEI and ARB may offer synergistic blockade of the RAS as it has been stated that the reduction of proteinuria was significantly greater when losartan was added. It has to be further determined by prospective studies, whereas this effect is associated with long-term kidney protection (Caletti et al., 2013, 2011). 2.5. Attention deficit hyperactivity disorder An interesting hypothesis considering unconventional use of ACEI is the one suggesting its potential positive effect in the treatment of attention deficit hyperactivity disorder (ADHD). There are studies suggesting that environmental exposure to lead contributes to ADHD. Lead can cause oxidative stress and inhibit energy production by inhibition of creatine kinase and pyruvate kinase. The latter can be associated 5

with the energy deficiency model of ADHD. Considering the antioxidant and chelating effects exerted by captopril, it is hypothesized that captopril may improve energy buffering and antioxidant capacity in ADHD. Although interesting, this hypothesis has not been investigated so far (Ghanizadeh, 2011).

3.

Neurology

3.1. Might ACEI help in neurological disorders? The RAS exists locally in many tissues in the body and in some its function is still unknown. The brain has also a local RAS, which is associated with neurodegenerative disorders. Inhibition of the brain RAS can be a potential therapeutic target for such neurological diseases as Parkinson’s disease, Alzheimer’s disease, dementia, cognitive decline or drug abuse (Goel et al., 2015; Labandeira-Garcia et al., 2012; Messerli et al., 2007).

3.2. Parkinson’s disease 1.5% world’s population aged over 65 suffers from Parkinson’s disease (PD). PD is a gradual decrease in the number of dopaminergic neurons in the substantia nigra and striatum. Treatment strategies are mostly based on providing neuroprotection by reversing or slowing down neurodegradation, which is responsible for motor dysfunction (Wright and Harding, 2012). Brain RAS can be an important target in PD because of a diverse spectrum of ACEI activity: antioxidant properties, modulation of hepatocyte growth factor (HGF), activation of NO synthase in the cells of hippocampal astroglia and the ability to increase the level of dopamine and to improve the response to its precursors. The Ang I receptors have been found on dopaminergic neurons and there is a significant interaction between Ang I and dopamine. PD occurs due to nigrostriatal degeneration and dopaminergic neuron loss, which is linked to a decreased number of Ang I receptors in the brain and that can be another crucial target for PD treatment (Labandeira-Garcia et al., 2012). ACEI that are active in the central nervous system simply boost the synthesis and release of striatal dopamine (Reardon et al., 2000). The reactive oxygen species (ROS) are highly toxic for the dopaminergic neurons, hence PD progression can be triggered by oxidative stress. Those ACEI that can penetrate the blood-brain barrier and thus are active in the central nervous system may serve as Parkinson’s disease treatment. The mechanism of their antioxidant action is based on the fact that angiotensin is one of the activators of NADPH-dependent oxidases, which are the source of ROS and are located throughout substantia nigra and striatum in the

6

brain. Thereby, the inhibition of synthesis of angiotensin protects cells from damage induced by free radicals (Munoz et al., 2006; Wright and Harding, 2012). The antioxidant properties and regulation of dopamine levels are not the only reasons why the ACEI may be beneficial in PD treatment. Also, the influence on HGF and its tyrosine kinase c-Met receptor creates new possibilities of action. The HGF glycoprotein is a mitogenic, morphogenic and motogenic growth factor that protects dopaminergic neurons. HGF/c-MET receptor pathway is a crucial system for motor and sensory neurons permanence. The use of HGF as a drug provides problems: very high costs of HGF production and improbability of reaching the desirable target where neuroprotection is needed (as it is improbable for a large glycoprotein to penetrate the blood-brain barrier (BBB)). This can be solved by substituting HGF with small molecule mimetics, like ACEI. Brain penetrating ACEI (Table 1) can activate the HGF system, elicit neuroprotection, and promote synaptogenesis. Table 1. The early investigations on the role of ACEI in the central nervous system revealed a connection between ACEI treatment in neurological diseases and better quality of life (Schölkens et al., 1983). Quality of life after ACEI treatment was measured by mood elevation (Zubenko and Nixon, 1984), subjective well-being (Croog et al., 1986; Deicken, 1986) or improvement of cognitive function like memory (Currie et al., 1990; Ho et al., 1978; Jenkins, 2008; Jenkins and Chai, 2007; Mashhoody et al., 2014; Wyss et al., 2003). The mechanism of this action is still unclear, nevertheless there is a strong positive correlation between the level of dopamine and the improvement of cognitive functions. The influence of ACEI on dopamine level is strong - one week long oral treatment with perindopril increased striatal dopamine levels in rats 2,5 times (Frcka and Lader, 1988; Jenkins et al., 1997, 1995). Research on patients with PD treated with perindopril proved that they had better motor response to dopamine precursors (Reardon et al., 2000; Wright and Harding, 2012).

3.3.

Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative brain disorder that results in dementia and personality changes, which affects more than 20 million people all over the world. AD starts slowly and short-term memory loss and unusual behaviour are the early symptoms. Neuropathological changes in patients’ brain are caused by amyloid β (Aβ) fibrillar deposits that change the synapse structure and disturb neuronal communication. According to the results of some investigations, ACEI can be a treatment for declining memory and cognitive functions (Arregui et al., 1982, 1979; Mendelsohn et al., 1984; Mondadori and Etienne, 1990). 7

AD treatment is also open for the use of ACEI as there is an evident correlation between brain RAS system and dementia. An increased activity of ACE has been observed in patients suffering from AD, which can be modulated by the use of ACEI that penetrate the BBB (Table 1) (Ohrui et al., 2004; Sink et al., 2009). Observational studies lead to a conclusion that brain penetrating ACEI slow the rate of cognitive functions decline in AD patients by 65%, in comparison to ACEI that do not penetrate BBB (Table 1) or calcium channel blockers. Among all the patients taking alternative anti-hypertensive drugs only the group taking captopril and perindopril had substantially lower risk of dementia and AD (Ohrui et al., 2004). This decrease of the risk of AD can be attributed to the reduction of oxidative stress and brain inflammation. Cerebral inflammation can be triggered by Aβ that accumulates in the brain of AD patients. Aβ is responsible for the activation of microglia, astrocytes, and also enhances oxidative stress leading to neuronal defect and diminution of cognition functions. The impact of Aβ on RAS is evident, since Aβ administrated directly into the brain tissue enhances ACE activity (Dong et al., 2011). Brain substance P (SP) is a crucial factor that has an influence on the level of Aβ. SP can enhance the activity of neprilysin, which is capable of degrading Aβ, ipso facto having a positive effect on the course of AD. ACEI increase the level of SP and thus decrease the accumulation of Aβ and resulting inflammation (Iwata et al., 2000; Ohrui et al., 2004). The exact investigation of the role of BBB penetrating ACEI in this process has been carried out using mice models. The main discovery in this study states that perindopril not only inhibits brain ACE but also is responsible for the impairment of glial activation and oxidative stress. Therapy with BBB penetrating ACEI may have a significant beneficial effect not only for the prevention but also for the treatment of mild to moderate AD (Arregui et al., 1982, 1979; Dong et al., 2011).

3.4.

Memory

Learning and memory processes in humans are very complex and engage numerous neurotransmitters. An important process of this pathway is regulated by the cholinergic neuronal system. Attenuation of memory can be caused by the anticholinergic agent, and scopolamine (SC) and ACEI can reduce or eliminate this action. Animals with scopolamine-induced amnesia demonstrate higher acetylcholinesterase (AChE) activity, which could be inhibited by ACEI (captopril, perindopril, enalapril and ramipril were investigated). SC treatment also increased levels of malondialdehyde (MDA) in animal brains and hence induced oxidative stress. ACEI pretreatment prevented oxidative stress by suppressing the MDA level (Mondadori and Etienne, 1990, Nikolova et al., 2000; Raghavendra et al., 2001). 8

3.5.

Migraine

Migraine is a complex disorder and there are a lot of controversies considering its treatment. Nevertheless, prophylactic drugs reducing headaches have great importance for patients not responding to triptans (about 40%). One of the drug groups taken into consideration as preventive agents is ACEI, as there is a correlation between the activity of RAS and migraine epizodes. Indeed, clinical investigations have generated evidence that the administration of certain ACEI (lisinopril, enalapril) diminishes the severity of those epizodes in hyper- and normotensive patients. It has been shown that use of ACEI resulted in the reduction of such parameters as hours with headache, days with headache, and days with migraine and the effect was higher by about 20% in comparison to a placebo group. Unfortunately, the mechanism of this action is still unknown, but it may involve alerting sympathetic activity, increased prostacyclin synthesis, stimulation of degradation of bradykinin, substance P or encephalin and strong antioxidative function. More tests in this field are needed. Nevertheless, ACEI might have a clinically important prophylactic effect in migraine (Bender, 1995; Schrader et al., 2001; Stanisz et al., 2014).

3.6.Stroke PROGRESS (Perindopril Protection Against Recurrent Stroke Study) (Ratnasabapathy et al., 2003) investigation and another independent analysis made by Chapman et al. (2004) proved that perindopril not only decreases blood pressure but also reduces the risk of stroke and cardiac problems. ACEI therapy is highly beneficial for patients with a history of stroke or transient ischemic attack and this effect can be seen also in non-hypertensive patients. The risk of cognitive impairment and dementia is strongly associated with the incident of stroke. Lowering blood pressure obviously reduces the risk of stroke itself, moreover, use of perindopril (especially in combination with indapamide) shows better effect than other anti-hypertensive drugs in patients with a history of a stroke incident, i.e., the risk of dementia could be reduced by 30% and the risk of cognitive decline – by 50%. As patients with cerebrovascular diseases have higher risk of coronary events and heart failure, ACEI are highly beneficial in reducing the risk of these disorders by more than 20% and decreasing the risk of a stroke by more than 40%. Perindopril could be considered as the first-line therapeutic agent for all the patients with cerebrovascular disorders since it does not cause hypotension nor renal dysfunction (Chapman et al., 2004; Ratnasabapathy et al., 2003; Reardon et al., 2000).

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3.7.

Drug abuse

Cognitive enhancement and possible anti-depressant and mood elevating activity are only some of the effects of ACEI, that are beneficial to a certain extent for the patients without hypertension (Bisio et al., 1990; Jenkins et al., 1997, 1995; Margolin et al., 2000). Taking into account that RAS has an impact on neural substrates and neurotransmitters such as dopamine and norepinephrine, it might be considered as a new target in the treatment of drug addiction. In this regard, pharmacotherapy with ACEI may be a new option not only because of the effect on the circulatory system but also due to its property of decreasing anxiety, attenuating drug-liking and stimulating dopaminergic systems (Kreek, 1996; Lijffijt et al., 2014; Verrico et al., 2016). The use of ACEI in addiction treatment has been the focus of scientists since the 1990s, when the influence of angiotensin on behaviour was discovered. Early studies conducted in rats and mice addicted to ethanol proved that the binding of Ang II to central AT-1 receptors is possibly responsible for drugseeking behaviour in addicts. Genetically modified mice over-expressing angiotensinogen showed greater alcohol consumption. In contrast, a reverse effect was observed in mouse models with genetically ablated angiotensinogen (Maul et al., 2005, 2001). Also injections of Ang II increase alcohol consumption (Fitts, 1993). The abuse of cocaine and presumably other drugs as well greatly increases ACE activity (Lingham et al., 1990; Verrico et al., 2016, 2013; Visniauskas et al., 2012). Increased blood pressure caused by methamphetamine or cocaine is proved to be mediated by AT-1 receptor and can be prevented by a low dose of ACEI. Furthermore, such therapy could be also beneficial in protecting against cardiac events or cardiotoxic effects of drugs. ACEI that have dopaminergic features can limit the use of cocaine by inverting or compensating for down-regulation in dopaminergic system consecutive to long-term drug use. Ang II is also responsible for the enhancement of the action of norepinephrine, which contributes to the effects of methamphetamine (Verrico et al., 2016). Moreover, it has been stated that withdrawal from cocaine abuse can activate corticotropin-releasing factor (CRF), which could be also one of the factors that enhance a chance of stress-related relapse to cocaine. ACEI reduce a release of CRF, contrary to Ang II that increases CRF levels (Aguilera et al., 1995; Zacharieva et al., 1991). Moreover, all the benefits from ACEI therapy can also apply to HIV-positive drug-abusing patients (Margolin et al., 2000). Another investigation reported that Ang II may influence the opioid system. The mechanism is based not only on changing dopamine levels but also on elevating the level of endogenous opioids. The confirmation of this hypothesis comes from the fact that the positive impact of ACEI on memory and learning can be overcome by naloxone (a drug used to block the effects of overdosing of opioids) (Jenkins et al., 1997; Millar et al., 1983). Hence Ang II injections in opioid abusing animals augmented the 10

withdrawal symptoms. The administration of captopril in rodents addicted to morphine diminished drug self-administration and withdrawal signs (Hosseini et al., 2009, 2007).

4. Arteriosclerotic vascular disease 4.1. Does RAS play a role in atherosclerosis? The wide spectrum of ACEI use is mainly possible due to the fact that their protective effect is associated with the repression of oxidative stress. Furthermore, blocking Ang II receptor may slow inflammatory processes. Ang II was reported to exert proinflammatory potential via stimulation of AT-1 receptors in leukocytes (Chang and Wei, 2015; da Silveira et al., 2010). RAS influences the way endothelium affects the generation of inflammatory cytokines (TNF-α), thrombosis and oxidative stress, which plays crucial role in atherosclerosis. It is known that Ang II can induce oxidant species generation by activating NADPH oxidase, which is related to the damage of the vascular system. Reactive oxygen species oxidize such biomolecules like lipids, lipoproteins and DNA, which in consequence leads to impaired endothelial function (Fig. 2). Fig.2. Studies proved that patients with renal and cardiovascular diseases have lower levels of tissue antioxidants and using ACEI decreases vascular inflammatory markers, thus reducing coronary atherosclerosis (Husain et al., 2015, 2010). The role of anti-inflammatory and antioxidant mechanisms of ACEI action is also widely discussed in modulation of rheumatoid arthritis (Wahba et al., 2015), hepatitis (Reza et al., 2016), nephropathy (Alderson et al., 2004) and reduction of the risk of retinopathy (Zheng et al., 2009).

5. Adipose tissue 5.1.

Is there a link between ACEI and obesity?

The rate of overweight and obesity has dramatically increased in the past years, reaching now epidemic range. The underlying mechanism of drastic weight gain in different societies remains unclear and available pharmacological treatment options are limited, thus the search for possible ways of prevention and therapy of obesity is of great importance for medicine. 11

ACEI have also gained importance in this field. There is a local RAS in adipose tissue, which is able to produce all the components of the system: angiotensinogen, ACE and AT1-R. The role of ACEI in the adipose RAS has not been taken into consideration for a long time, however, today the adipose tissue and Ang II are considered as one of the most important sites for inflammatory and endocrine regulation of appetite. Active adipose RAS and Ang II have been shown to play important roles in adipocyte growth and differentiation, thus local RAS can be a link between obesity and hypertension. High activity of the system increases the risk of cardiovascular disorders and insulin resistance. So it is not surprising that reducing RAS activity can be beneficial in treating obesity and improving insulin sensitivity. ACEI (perindopril, captopril, enalapril and ramipril) were reported to have a weight loss effect in animals as well as in humans. Treatment with ACEI in normotensive rats resulted in reduction of body weight by decreasing food intake, increasing leptin levels and improving insulin sensitivity, as well as diminishing mRNA expression of markers of inflammation, which was independent of any blood pressure lowering effects or modifications in serum lipid profile (Premaratna et al., 2012; Santos et al., 2008; Segura and Ruilope, 2007; Stanisz et al., 2014; Velkoska et al., 2010).

6. Genetics 6.1.

Has the ACE polymorphism any importance for patients?

ACE as previously mentioned is a crucial player in the RAS. The main role of ACE is to convert angiotensin I (1-10) to angiotensin II (1-8) and this reaction is targeted by ACE inhibitors (Fig. 1). The effectiveness of such transformation is regulated by ACE2, an isoenzyme of ACE that converts Ang I (110) to Ang (1-9) that is further modified to Ang (1-7) (Guang et al., 2012). However, over the past quarter of century much attention has been paid to the issue of ACE polymorphism. In 1990 Rigat and co-workers described an insertion/deletion (I/D) polymorphism in the ACE gene. Gelblot hybridization experiments made on genomic DNA after exposure to restriction enzyme led to identification of two variants of different length, approximately 9250 and 9500 bp, which was related to deletion and insertion of polymorphic variants, respectively. In a group of 80 healthy subjects nearly half were heterozygotes (ID, n = 37), fewer were homozygotes with the shorter allele (DD, n = 29), while longer allele homozygotes were in minority (II, n = 14) (Rigat et al., 1990). ACE is located on chromosome 17, consists of 26 exons and the I/D polymorphism concerns intron 16 in which a precisely 287 bp long insertion corresponds to the Alu repetitive sequence (Hubert et al., 1991; Tiret et al., 1992). The I/D variants of ACE were initially associated with differences in ACE serum levels. In detail, the DD genotype presented the highest, the ID genotype moderate and the II genotype the lowest concentration of

12

ACE, which confirms the implication of the I/D polymorphism in the control of circulating ACE level (Rigat et al., 1990; Tiret et al., 1992). The I/D polymorphism analysis became “trendy” and was evaluated in many variable aspects as soon as the relation to ACE activity was known. Below selected examples are presented. The deletion variant (DD) of ACE gene has no correlation with either the increase in the risk of ischemic heart disease or myocardial infarction (Lindpaintner et al., 1995). On the other hand, the insertion variant (II) of ACE has been shown to be strongly associated with the risk of psoriasis, but only in male patients (Munir et al., 2016). The DD genotype is potentially a risk factor for chronic kidney failure among hypertensive patients (Sarkar et al., 2016). In addition, the II genotype may present a protective effect against migraine in some populations (Wan et al., 2016). Results of meta-analyses concerning several disease entities are collected in table (Table 2). The I/D polymorphism sometimes is compared with other genetic variants like single nucleotide polymorphism (SNP). In the case of acute respiratory distress syndrome (ARDS), the DD genotype was statistically correlated with death risk, while -6A/G angiotensinogen promoter polymorphism presented no association (Adamzik et al., 2007). Moreover, neither the I/D polymorphism nor Ang II AT1-R 1166A/C SNP are related to multiple sclerosis, but Ang II receptor type 2 (AT-2R) -1332A/G SNP (AA variant) may be a genetic risk factor in females in this disease (Živković et al., 2016). Despite the initial promising results about the I/D polymorphism in cardiovascular field, further contradictory results reduced the expectations about ACE genotyping (Pinto and van Gilst, 1999). The I/D variants only partialy regulate ACE level (Rigat et al., 1990) or are even irrelevant for the RAS (Danser et al., 2007). Furthermore, some other mechanisms such as epigenetic regulation might control ACE gene in a more accurate way (Raleigh, 2012). Also other genetic changes can more effectively orchestrate circulating ACE level and blood pressure. Zhu and co-workers (2001) analysed 12 different SNPs besides the I/D polymorphism. They found strong evidence for the association between two SNPs in the ACE gene and the concentration of circulating-ACE, namely ACE4 (-262A/T in 5’ untranslated region) and the most significant ACE8 (11860A/G in exon 17). The co-existence of both SNPs was also correlated with changes in blood pressure (Zou et al., 2011). Is there any correlation between ACEI efficacy and genetic variants of the RAS genes? The results are variable. Anti-proteinuric effects of ACEI (benazepril 10 mg/day or perindopril 4 mg/day) in patients with proteinuria related to non-insulin-dependent diabetes mellitus were compared by assessing the ACE insertion/deletion genotype. This study highlighted the DD genotype as a genetic marker of good response (Ha et al., 2000). On the contrary, in patients receiving perindopril (2 mg/day for 2 weeks, followed by 4 mg/day for 2 weeks) none of the ACE genotypes was associated with blood pressure reduction and 13

cardiovascular benefits (Harrap et al., 2003). Quite interesting observations were made in relation to ACEI-related cough. For Chinese female patients with non-insulin-dependent diabetes mellitus, there was much higher correlation between II genotpye and this side effect than between the ID or the DD genotype. As high incidence of cough related with ACI therapy is observed in Chinese and African-American-origin patients thus genotyping may be helpful in drug selection (Lee and Tsai, 2001). Also SNPs were identified to provoke differences in the effects of therapy with ACEI. ACE 2350A/G, but not ACE -240A/T or the I/D polymorphism may generate renoprotective effects in IgA nephropathy (Narita et al., 2003). Several other genetic determinants of perindopril treatment are of benefit in patients with stable coronary artery disease, such have been described for Ang II AT1-R or bradykinin receptor type 1 and can be useful in optimization of pharmacotherapy (Brugts et al., 2010). In conclusion, effects of the I/D polymorphism and SNPs are varied. Many experiments have shown no correlation with different analysed features. However, in particular fields there are some results, which can be potentially used in clinical practice.

Table 2.

7. Cancer 7.1.

How ACE meets neoplasia?

Cancer as a collective term includes a wide range of diseases occurring as an effect of accumulation of genetic and epigenetic changes forcing malignancy in various tissues and organs. According to Hanahan and Weinberg (2011), the hallmarks of cancer are insensitivity to anti-growth signals, self-sufficiency in growth signals, loss of capacity for senescence and apoptosis, induction of angiogenesis, invasiveness and metastasis, immune destruction avoidance of cancer cells and reorganization of energy metabolism. The RAS may affect basal processes of tumor initiation and development based on its engagement in many different regulatory pathways. Both the systemic and local RAS activity needs to be taken into consideration. Systemic effects are related to the well-known function of the RAS, i.e., vasoconstriction of arterioles, regulation of water and electrolytes balance, all of which affect blood pressure (effects dependent on the stimulation of Ang II AT-1R). However, the local RAS systems also regulate many important cell and tissue processes (Carey and Siragy, 2003; George et al., 2010; Regulska et al., 2013). A wide range of connections between the RAS and carcinogenesis has been recently discussed. In brief, the impact of the RAS activation on cancer biology results from its engagement in: 1) cellular proliferation 14

and apoptosis (e.g. activation of AT1-R stimulates PI3K/Akt pathway or EGFR); 2) invasion, migration and metastasis (e.g. metalloproteinase upregulation); 3) inflammation and oxidative stress (e.g. release of pro-inflammatory mediators like TNF-α, ROS and various prostaglandins, also in response to viruses, bacteria and parasites invasions); 4) forcing cancer cachexia (e.g. related to the release of inflammatory cytokines); and 5) angiogenesis stimulation (Regulska et al., 2013). The last process seems to be one of the most promising objectives for the anti-RAS therapy. AT-1R stimulation is followed by enhanced expression and activity of vascular endothelial growth factor (VEGF), VEGF receptor and epidermal growth factor receptor (EGFR) (Takai et al., 1997), which can support angiogenesis in acidified microenvironment, occurring as a result of oxidative glycolysis (so called Warburg effect), which generates lactate leading to an increase in HIF-1α and c-MYC pro-tumorigenic transcription factors (Kleszcz et al., 2015). Neovascularization provides the growing tumor not only with metabolites and oxygen, but also enables metastasis. This process may be influenced by ACEI (Sugimoto et al., 2012). Based on a 10-year retrospective study of patients taking anti-hypertensive drugs targeting the RAS (mainly ACEI) a statistically significant decrease in the risk of cancer was observed (Lever et al., 1998). Likewise, in vitro studies seem to confirm the anti-angiogenic role of ACEI. For instance, the exposure of BNL-HCC cells (adherent chemically transformed mouse liver cell line) to perindopril caused the down-regulation of the VEGF mRNA and a decrease in VEGF protein levels (Yoshiji et al., 2001). However, in vivo study did not find a significant difference in tumor weight and vascularization in esophageal carcinoma xenograft model (to establish xenografts the EC9706 cell line with high VEGF mRNA expression was used) between perindopril and control group, but on the other hand showed positive effects for another ACE inhibitor - benazepril (Wang et al., 2012). In turn, captopril treatment significantly decreased tumor growth and lymph node metastasis in LNM35 human lung cancer cells mice xenograft model, but results were not associated with angiogenesis inhibition, but rather resulted from apoptosis induction (Attoub et al., 2008). In addition, anti-angiogenic mechanisms unrelated to ACEI have been detected in the inhibition of most metalloproteinases and generation of angiostatin (Regulska et al., 2013; Yoshiji et al., 2001). These findings support the anti-tumor potential benefit of ACE inhibitors irrespective of the detailed molecular mechanism. Previously the role of the insertion/deletion (I/D) polymorphism in the ACE gene has been discussed. The results are inconclusive but suggest that the DD genotype is the undesirable genetic variant in many diseases. Similar analysis has been performed with respect to cancer. The DD genotype significantly increased the susceptibility to oral cancer and lymph node metastasis in male betel quid chewers (Liu et al., 2012). Moreover, the DD genotype was slightly more frequent (51.7 vs 44.4%, p=0.036) in patients with hepatocellular carcinoma (Chinese Dai population) than in control population (Zha et al., 2015). In 15

gastric cancer the number of lymph node metastasis was significantly higher for the DD genotype carriers (Röcken et al., 2005). On the other hand, the II genotype was identified as a risk factor for pancreatic cancer development, while the DD genotype was associated with higher probability of chronic pancreatitis (Lukic et al., 2011). It is also indicated based on clinical practice that receiving the RAS inhibitory drugs protects some patients from breast cancer (van der Knaap et al., 2008). On the other hand, there are many results showing no statistical correlation between the I/D polymorphism and cancer. No association has been found in case of gastric cancer risk in Japanese population (Hibi et al., 2011; Sugimoto et al., 2006) or benign uterine leiomyoma in Turkish population (Gültekin et al., 2015). Meta-analysis results are discursive, too. Available results support the II genotype protective functions in gastric cancer (Pabalan et al., 2015), while results of meta-analysis for lung cancer deny any correlation (Cheng et al., 2015). Finally, meta-analysis that concerned the general I/D polymorphism association with the risk of cancer confirmed rather a tendency than statistical significance for the DD genotype negative role, because a large variation of results was observed (Ruiter et al., 2011). Thus the I/D polymorphism cannot be universally used to predict tumorigenesis fate, but widespread clinical use of ACEI and other RAS modulators may also bring benefits in the oncology field (Fig. 3). Fig. 3.

8.

Conclusion

ACEI show variable and complex biological activities, which determine the diversity of possible clinical use. Their antioxidant activity, which is related to their ability to suppress the activity of NADPH oxidase, an enzyme responsible for ROS generation and the production of proinflammatory mediators, has emerged as a pharmacologically extremely important factor, since oxidative stress is the precursor of many pathologies and disorders. The widespread use of ACEI may be extended beyond hypertension and cardiovascular diseases in adults and children, and concerns also patients with inflammatory diseases, neurological disorders, drug abuse, cancer, diabetes, obesity or atherosclerosis. To understand the mechanisms and complexity of the subject we have to answer the questions about the role of genetic factors. The importance of the insertion/deletion (I/D) polymorphism as well as SNPs for the ACE gene regulation remains controversial, but a general tendency for the DD genotype (less often II genotype) negative role may provide direction to development of the novel treatment for some particular illnesses.

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As hypertension is one of the most common diseases of the circulatory system all over the world and antihypertensive drugs are the most frequently prescribed group of medicines, it should be taken into account that using ACEI has many advantages besides hypertension treatment, especially for patients in advanced age and with comorbidities. All beneficial effects described in the article should be further investigated and validated by clinical trials. Results of such trials can show clearly if ACEI are able to give long-term benefits for patients besides its anti-hypertensive effects.

The study was financially supported by Poznan University of Medical Sciences Academic Grant for Young Scientists (No. 502-14-03305411-41169).

Declaration of conflicting interests The authors declare no conflicts of interests.

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Fig. 1. The renin-angiotensin system (RAS) main pathway and the role of angiotensin converting enzymes (ACE) inhibitors Fig. 2. The role of RAS overactivity in pathogenesis of atherosclerosis Fig. 3. RAS and its metabolite-dependent mechanisms related to promotion of malignancy (for detailed explanation, see the text)

Table 1 Classes of ACEI penetrating or non penetrating the blood-brain barrier (BBB) (Sink et al., 2009)

ACE inhibitor penetrating the blood-brain barrier

ACE inhibitor nonpenetrating the blood-brain barrier

Captopril

Ramipril

Perindopril

Quinapril 31

Fosinopril

Moexepril

Lisinopril

Enalapril

Trandolapril

Benazepril

Zofenopril

Table 2. An overview of meta-analysis results concerning ACE I/D polymorphism

DISEASE/FEATURE

ASSOCIATION

REFERENCE

pregnancy-induced hypertension

higher risk for DD genotype

Miao and Gong, 2015

Behcet disease

higher risk for DD genotype

Mandal et al., 2013

vitiligo

higher risk for DD genotype

Lv et al., 2013

coronary heart disease (the Chinese population)

higher risk for DD genotype

Zhou et al., 2012a

higher risk for DD genotype

Qu et al., 2001

higher left ventricular mass for DD genotype

Jin et al., 2011

higher left ventricular mass for DD genotype

Kuznetsova et al., 2000

essential hypertension (in Chinese population) echocardiographic left ventricular structure left ventricular hypertrophy cerebral infarction vesicoureteral reflux susceptibility in children end-stage renal disease (patients with diabetic nephropathy) ischemic stroke

higher risk for DD genotype (Han Chinese population) higher risk for DD genotype (only in the Turkish population) higher risk for D allele & DD genotype (Asians) / DD genotype (Caucasians) higher risk for DD genotype (weak correlation for Caucasians)

Tao et al., 2009 Zhou et al., 2012b Yu et al., 2012 Zhao et al., 2014

IgA nephropathy

higher risk for DD genotype (Asian) no association (Caucasian)

Qin et al., 2011

bipolar disorder

higher risk for DD genotype (Asian) no association (Caucasian)

Zou et al., 2011

Alzheimer's disease

lower risk for DD genotype

Lehmann et al., 2005

no marked association

Zhou et al., 2011

no marked association

Kitsios and Zintzaras, 2009

no association

Pereza et al., 2016

no association

Feng et al., 2013

idiopathic nephrotic syndrome (Asian children) response to treatment in coronary artery disease idiopathic recurrent spontaneous abortion obstructive sleep apnea-hypopnea syndrome

32

vascular dementia

no association

Liu et al., 2009

progression of renal failure in autosomal dominant polycystic kidney disease

no association

Pereira et al., 2006

33

Figure

H2N

Asp

Arg

Val

Tyr

Ile

His

Pro

Phe

His

Leu

+443 aa

ANGIOTENSINOGEN

RENIN

H2N

Asp

Arg

Val

Tyr

Ile

His

Pro

Phe

His

Leu

COOH

ANGIOTENSIN I (1-10)

ACE inhibitors H2N

Asp

Arg

Val

Tyr

Ile

ACE

inactive metabolites His

Pro

Phe

ANGIOTENSIN II (1-8)

AT1

RECEPTOR

BRADYKININ (9 aa)

effects of AT1 receptor activation

COOH

Figure

RAS

activity ↑ inflammation & oxidative stress by release of inflammatory mediators e.g. TNF-α, ROS or ↑ NADPH oxidase

↑ oxidization of biomolecules (i.e. lipids, lipoproteins and DNA)

ATHEROSCLEROSIS

endothelial impairment

Figure

MALIGNANCY HOMEOSTASIS

↑ cellular proliferation ↓ apoptosis & differentation e.g. by activation of PI3K/Akt pathway, EGFR, BCL-XL, survivin

RAS

activity

↑ invasion, migration & metastasis e.g. by activation of PKA, PKC, PI3K/Akt pathway

BIOLOGICAL EFFECTS

↑ inflammation & oxidative stress by release of inflammatory mediators e.g. TNF-α, NF-κB, MMPs, ILs, ROS

↑ CACHEXIA (wasting syndrome) ↑ angiogenesis (↑ delivery of O2 & metabolites) e.g. by ↑ VEGF, VEGFR, EGFR

the Warburg effect

↑ eNOS

LACTATE acidic & hypoxic microenvironment

↑NO

HIF-1 VHL mutation

prolyl hydroxylase 2

mutations in CAC SUCCINATE, FUMARATE, 2-HYDROXYGLUTARATE