APJ system: A bifunctional target for cardiac hypertrophy

IJCA-24077; No of Pages 7 International Journal of Cardiology xxx (2016) xxx–xxx

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Review

Apelin/APJ system: A bifunctional target for cardiac hypertrophy Liqun Lu 1, Di Wu 1, Lanfang Li ⁎,2, Linxi Chen ⁎,2 Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang 421001, China

a r t i c l e

i n f o

Article history: Received 1 September 2016 Accepted 6 November 2016 Available online xxxx Keywords: Apelin/APJ system Cardiac hypertrophy Oxidative stress Obesity Hypertension Myocardial infarction

a b s t r a c t Apelin acts as the endogenous ligand of G protein coupled receptors APJ. The apelin/APJ system is responsible for the occurrence and development of cardiovascular diseases. In recent years, apelin/APJ has been considered to play an important role in cardiac hypertrophy, but whether that role is beneficial or aggravating remains controversial. Apelin/APJ alleviates cardiac hypertrophy which is triggered by angiotensin II, oxidative stress and exercise. However, central administration of apelin induces cardiac hypertrophy. Peripheral administration of apelin also promotes the development of cardiac hypertrophy under non-pathological conditions. Furthermore, our laboratory discovers that apelin/APJ is able to induce hypertrophy of cardiomyocytes in vitro. The exact mechanism of apelin/APJ's dual effects in cardiac hypertrophy requires further study. In this paper, we review the controversies associated with apelin/APJ in cardiac hypertrophy and we elaborate the role of apelin/APJ in cardiac hypertrophy related-diseases including obesity, diabetes, hypertension, myocarditis and myocardial infarction. We conclude that further studies should emphasize more about the relationship between apelin/APJ and pathological hypertrophy especially in clinical patients. Moreover, apelin/APJ can be a promising therapeutic target for cardiac hypertrophy. © 2016 Published by Elsevier Ireland Ltd.

1. Introduction APJ, first identified in 1993, is a seven trans-membrane G protein coupled receptor. Its amino acid sequence has a strong homology with that of angiotensin II type 1 receptor (AT1R) (54% in transmembrane domains and 30% for the entire sequence). Angiotensin II (Ang II) has an affinity for AT1R but is not able to bind with APJ [1]. APJ remained orphaned until its endogenous ligand apelin was extracted from bovine stomach for the first time in 1998 [2]. Preproapelin, which consists of 77 amino acids, can be hydrolyzed by endopeptidases into several shorter C-terminal bioactive peptides, such as apelin-12, -13, -17 and -36 [3]. Proprotein convertase subtilisin/kexin3 (PCSK3) can also directly and preferentially cleave proapelin into apelin-13 in vitro, with no

Abbreviations: AT1R, angiotensin II type 1 receptor; Ang II, angiotensin II; PCSK3, proprotein convertase subtilisin/kexin3; 5-HT, serotonin; TNF-α, tumor necrosis factora; HW/BW, the ratio of heart weight/body weight; ANP, atrial natriuretic peptide; LV, left ventricular; ANF, atrial natriuretic factor; TGF-β1, transforming growth factor beta1; ROS, reactive oxygen species; β-MHC, beta-myosin heavy chain; HFD, high-fat diet; ER, endoplasmic reticulum; FA, fatty acid; MI, myocardial infarction; ACE2, angiotensinconverting enzyme 2; LVH, left ventricular hypertrophy. ⁎ Corresponding authors. E-mail addresses: [email protected] (L. Li), [email protected] (L. Chen). 1 Liqun Lu and Di Wu contributed equally to this work. 2 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

evidence of longer isoforms [4]. Furthermore, apelin-13 can be posttranslationally modified to produce the pyroglutaminated apelin-13 ([Pyr1]-apelin-13) which is much more stable than apelin-13 because it can prevent degradation of exopeptidases [5]. Apelin and APJ have been extensively distributed in central nervous system and peripheral tissues. Likewise, it has already been investigated that the apelin/APJ system has abundant biological functions such as facilitating angiogenesis, maintaining fluid homeostasis and regulating energy metabolism [3,6–9]. Within the cardiovascular system, apelin/ APJ is able to induce peripheral and coronary vasodilatation, lower the arterial blood pressure, decrease cardiac preload and afterload and increase cardiac output [10–12]. Furthermore, the apelin/APJ system plays overt roles in cardiac hypertrophy [13–17]. Here, we review recent studies about the relationship between the apelin/APJ system and cardiac hypertrophy. Cardiac hypertrophy is supposed to be an adaptive response to acute and chronic hemodynamic overload. Neurohumoral ingredients such as serotonin (5-HT), Ang II, tumor necrosis factor-a (TNF-α) and leptin are also responsible for the appearance of cardiac hypertrophy [13,18–20]. The increased protein synthesis in the cardiomyocytes, the augmented size of cardiomyocytes and the elevated ratio of heart weight/body weight (HW/BW) act as the main features of cardiac hypertrophy [14]. In recent years, apelin/APJ has been shown to play an important role in cardiac hypertrophy, but whether that role is beneficial or aggravating remains controversial. In this paper, we elaborate the intricate

http://dx.doi.org/10.1016/j.ijcard.2016.11.215 0167-5273/© 2016 Published by Elsevier Ireland Ltd.

Please cite this article as: L. Lu, et al., Apelin/APJ system: A bifunctional target for cardiac hypertrophy, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.11.215

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relationship between apelin/APJ and cardiac hypertrophy. Furthermore, we illuminate the role of apelin/APJ in cardiac hypertrophy relateddiseases including obesity, diabetes, hypertension, myocarditis and myocardial infarction. 2. Apelin/APJ alleviates Ang II –induced cardiac hypertrophy Ang II is certain to induce cardiac hypertrophy [21,22]. Ye et al. demonstrated that apelin over-expression abolish Ang II induced-cardiac hypertrophy by dramatically decreasing cell size, protein content and atrial natriuretic peptide (ANP) expression in cultured cardiomyocytes [23]. Iwanaga et al. established the model of hypertensive heart failure by using Dahl salt-sensitive rats. They discovered that the apelin/APJ system showed no change at the compensatory hypertrophic stage compared with control animals. The cardiac apelin system is markedly down-regulated in experimental heart failure stage and may be regulated by the Ang II–AT1R system directly. Inhibition of the renin– angiotensin system may have beneficial effects, at least in part, through restoration of the cardiac apelin system [24]. Ang II-treated wild-type mice showed an increase in left ventricular (LV) mass, cardiomyocyte cross-sectional area and expression of atrial natriuretic factor (ANF). In contrast, TGF-β1 (transforming growth factor beta1)-deficient mice subjected to chronic subpressor doses of Ang II had no significant change in these markers of cardiac hypertrophy [22]. These results indicate that TGF-β1 may contribute to Ang II induced-cardiac hypertrophy. Apelin over-expression abolished Ang II induced-increase in TGF-β expression [23]. In addition, apelin can inhibit the elevation of TGF-β1 induced by renal ischemia/reperfusion injury in rats and cultured renal mesangial and tubular cells [25]. All of these findings indicate that apelin/APJ may alleviate Ang II induced-cardiac hypertrophy by reducing the levels of TGF-β1. (Fig. 1). 3. Apelin/APJ ameliorates oxidative stress-induced cardiac hypertrophy Oxidative stress is related to cardiac hypertrophy. Excessive production of ROS as well as reduction of cardiac antioxidant capacity plays a critical role in the progression of cardiac hypertrophy. It has already been shown that mechanical stress promotes cardiac hypertrophy through elevating intracellular reactive oxygen species (ROS) generation

Fig. 1. The bifunctional effects of apelin/APJ system in cardiac hypertrophy. On one hand, the apelin/APJ system is able to induce cardiac hypertrophy through PI3k-Akt-ERK1/2p70S6K pathway or via up-regulating the levels of ROS of cardiomyocytes; On the other hand, the apelin/APJ system can alleviate cardiac hypertrophy via PI3k-Akt-mTORp70S6K pathway or through inhibiting the expression of TGF-β1 or the generation of H2O2.

[26]. ROS is also involved in cardiomyocyte hypertrophy caused by Ang II, TNF-α, leptin and endothelin-1 [18–20,27]. Bianchi et al. demonstrated that 5-HT induces cardiomyocyte hypertrophy via an intracellular signalling pathway involving H2O2 generation [28]. And then Foussal et al. found that apelin markedly reduced 5-HT- induced or H2O2-induced oxidative stress. Apelin not only inhibits the production of ROS significantly but also promotes the antioxidant capacity by inducing the activity and expression of catalase in neonatal cardiomyocytes. Catalase is an antioxidant enzyme responsible for alleviating oxidative stress [13]. Therefore, apelin/APJ is able to inhibit oxidative stress-linked cardiac hypertrophy. (Fig. 1). 4. Apelin/APJ attenuates exercise-induced pathological cardiac hypertrophy Exercises can cause adaptive changes to myocardium in terms of cardiac morphology and function, leading to the occurrence of cardiac hypertrophy [29]. Long-term high intensity exercise training would cause cardiac hypertrophy accompanied by myocardial damage, entailing a risk of pathological changes. Liao et al. confirmed that Akt, mTOR and p70S6K were significantly activated in moderate exercise groups, which showed no pathological damage in myocardium. However, Akt, mTOR and p70S6K were not activated in high-intensity exercise groups, which may contribute to pathological cardiac hypertrophy [30]. Furthermore, PI3K/Akt signalling is activated in exercise-induced physiological cardiac hypertrophy [31]. Akt1 acts as a pivotal regulatory switch that promotes physiological cardiac hypertrophy while antagonising pathological hypertrophy [32]. Zhang et al. also verified that the apelin/APJ system can activate PI3K/Akt/mTOR signalling in PASMCs under hypoxia [33]. It has been found that the apelin/APJ system also promotes PI3K/ Akt signalling transduction pathway in VSMCs and endothelial progenitor cells [34,35]. Therefore, these results hint that apelin/APJ may prevent pathological cardiac hypertrophy connected with exercise via activating the PI3K/Akt/mTOR /p70S6K pathway. (Fig. 1). 5. Apelin/APJ is likely to induce the occurrence of cardiac hypertrophy Murata et al. demonstrated that overexpression of APJ causes cardiac hypertrophy and contractile dysfunction in male and non-pregnant mice [36]. Zhang et al. injected an adeno-associate virus containing apelin gene into the rostral ventrolateral medulla of normotensive rats. They found that the ratio of HW/BW and the cardiomyocyte cross-sectional areas significantly increased after 14 days, which means that overexpression of apelin results in remarkable cardiac hypertrophy [37]. Furthermore, after chronic infusion of apelin-13 into paraventricular nucleus of normotensive rats for 15 days, apelin-13 promoted the expression of myocardial ANP and β-MHC (beta-myosin heavy chain) mRNA, which indicates that apelin-13 can induce cardiac hypertrophy [38]. Rats were treated with pyroglutamylated apelin-13 intraperitoneally for 17 days, and the ratio of HW/BW elevated compared with the control group [39]. Li et al. discovered that the end-diastolic pressure and end-diastolic pressurevolume relationship were significantly increased when mice were treated with apelin-13 intraperitoneally for 14 days. These results indicate that apelin-13 may cause cardiac hypertrophy, which leads to diastolic dysfunction [40]. Taken together, these results suggest that long-term central or peripheral administration of apelin induces cardiac hypertrophy under non-pathological condition. Furthermore, our laboratory elaborated that apelin-13 promoted myocardial hypertrophy in vitro. PI3k-Akt-ERK1/2-p70S6K pathway was involved in apelin-13 induced-myocardial hypertrophy. Specific inhibitors of PI3k, Akt and ERK reversed the effects of apelin-13 on cardiomyocytes diameter, volume and protein contents [15]. (Fig. 1) Furthermore, Li et al. confirmed that apelin-13 can significantly up-regulate the levels of ROS in VSMCs in a concentration- (non-physiological 500– 2000 nM) and time-dependent manner [41]. Our laboratory found that

Please cite this article as: L. Lu, et al., Apelin/APJ system: A bifunctional target for cardiac hypertrophy, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.11.215

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apelin-13 increased the levels of ROS in H9c2 cardiomyocytes as well (this result has not been published). Therefore, Apelin-13 may promote myocardial hypertrophy through the mechanism of oxidative stress. However, Foussal et al. indicated that physiological 1–100 nM apelin markedly reduced oxidative stress by inhibiting H2O2 generation in neonatal cardiomyocytes [13]. (Fig. 1) Here, we speculate that different concentrations of apelin may cause opposing effects on oxidative stress. 6. Apelin/APJ is involved in disease associated with cardiac hypertrophy

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hypertrophy to heart failure was associated with reduced fatty acid (FA) utilization, accelerated glucose oxidation and mitochondrial damage. Treatment of HFD-fed mice with apelin prevented pressure overload-induced decline in FA metabolism and mitochondrial defects. Furthermore, apelin treatment lowered fasting plasma glucose, improved glucose tolerance and preserved cardiac function in HFD-fed mice subjected to pressure overload [49]. Taken together, apelin plays a vital role in regulating cardiac energy metabolism during the transition from cardiac hypertrophy to heart failure in obesity. (Table 1).

6.1. Obesity

6.2. Diabetes

Obesity has already been recognised as an independent risk factor for cardiac hypertrophy [42]. Apelin is able to alleviate or to reverse obesity associated cardiac hypertrophy. In the light of that fact, Ceylan-Isik et al. proved that high-fat diet (HFD) increased the cardiomyocyte cross-sectional area and the expression of GATA4 (marker of cardiac hypertrophy), which were attenuated by apelin [16]. Moreover, endoplasmic reticulum (ER) stress causes intracellular Ca2+ dysregulation and activates calcineurin-NFAT3 signalling pathway, resulting in cardiac hypertrophy [43]. Ceylan-Isik et al. also found that HFD promoted ER stress in the heart as evidenced by increased levels of Bip and CHOP (markers of ER stress), which were markedly attenuated by the administration of apelin [16]. Sawane et al. demonstrated that apelin inhibited HFD-induced obesity by enhancing lymphatic and blood vessel integrity [44]. Moreover, Guo et al. expounded that apelin-13 decreased lipid storage in hypertrophic adipocytes through the up-regulation of AQP7 expression. AQP7 is a water-glycerol transporter, presenting in the plasma membrane of adipocytes and playing a significant role in facilitating glycerol transport out of adipocytes, leading to a reduction in the cytoplasmic triglycerides levels [45]. This finding indicates that apelin is supposed to inhibit the occurrence of obesity via decreasing lipid storage, accounting for the beneficial effects of apelin on cardiac hypertrophy associated with obesity. Impaired energy metabolism is the defining characteristic of obesityrelated heart failure. Apelin has a role in the regulation of cardiovascular and metabolic homeostasis and may contribute to the link between obesity, energy metabolism and cardiac function [46–48]. Alfarano et al. found that in HFD-fed mice, pressure overload-induced transition from

It has been reported that diabetes share a responsibility for causing cardiac hypertrophy. Guo et al. treated experimental mice with streptozotocin to induce type I diabetes by causing acute insulin deficiency. Type I diabetes led to the increase of the cardiomyocyte crosssectional area. Peak shortening, maximal velocity of shortening and relengthening were significantly reduced in type I diabetes mice. These results indicate that type I diabetes can lead to cardiac hypertrophy and cardiac anomalies [50]. Of note, Akcilar et al. used alloxan to induce diabetes and they showed that the ratio of HW/BW was found to be higher in alloxan-induced diabetic group than in the control group, which implies that alloxan-induced diabetes may cause cardiac hypertrophy [39]. However, alloxan is more likely to induce type I (lack of insulin) than type II (insulin resistance) diabetes since it can destroy βcells [51]. So far, studies have evaluated that apelin can show overt significance in ameliorating diabetes related-cardiac hypertrophy. Increasing capillary density induced by apelin gene therapy has been shown to reverse cardiac hypertrophy in type II diabetes [52]. Apelin treatment significantly lowers blood glucose and protects HFD mice from hyperinsulinemia. Furthermore, apelin−/− mice fed a HFD are insulin resistant [53]. Apelin restores glucose tolerance and increases glucose utilization in obese and insulin-resistant mice [54]. Apelin stimulates glucose uptake and improves insulin resistance in 3T3-L1 adipocytes [55]. Similarly, it has also been reported that apelin plays a corroborative role in improving the sensitivity of insulin, regulating glucose metabolism and facilitating peripheral glucose uptake [3,56,57]. In view of that, apelin is endowed with anti-diabetic properties and can be used as a therapeutic agent in the treatment of type I and type II diabetes in the near future. (Table 1).

Table 1 Apelin is involved in disease associated with cardiac hypertrophy. Disease types

Experiment models

Treatment

Pathway

Effects

Reference

Obesity

Mice in vivo

HFD HFD + Apelin Apelin-13 HFD HFD + Apelin Streptozotocin Alloxan Apelin Apelin AngR antagonist/ACE inhibitor Apelin Apelin Specific TLR4 blocker Apelin Knockdown apelin [Pyr1]-apelin-13 Apelin-12 LAD ligation LAD ligation + Apelin-13 Apelin

↑ER stress ↓ER stress ↑AQP7 ↓FAO ↑GLUO ↑FAO ↓GLUO Cause Insulin deficiency Destroy pancreatic beta cells increase glucose utilization Improve insulin sensitivity Lower blood pressure ↓RAAS ↑ACE2 ↓Myocardial inflammation ↑PI3K/Akt ↑MEK/Erk ? ↓Oxidative injury ↑NO ? ? ? ↑Sirt3

↑CH ↓CH ↓Lipid storage ↑CH to HF ↓CH to HF ↑CH ↑CH Anti-diabetes Anti-diabetes ↓LVH ↓Blood pressure ↓CH ↓CH ↑Inflammatory cytokines ↑Inflammatory cytokines ↓Myocardial damage Limit MI size ↑CH ↓CH ↓CH

[16] [16] [45] [49] [49] [50] [39] [54] [55] [59] [62] [66] [60] [72] [73] [76] [77] [40] [40] [78]

Hypertrophic adipocytes Pressure overload mice Diabetes

Hypertension

Myocarditis

Myocardial infarction

Mice in vivo Rats in vivo Obese and insulin resistant mice 3T3-L1 adipocytes Patients with LVH Hypertensive rats The failing hearts Ang II-infused rats BV2 cells in vitro Primary amnion cells A rat model of MI Rats in vivo Post-MI mice in vivo Post-MI mice in vivo

CH: cardiac hypertrophy. FAO: fatty acid oxidation. GLUO: glucose oxidation. CH to HF: the transition from cardiac hypertrophy to heart failure. AngR: Angiotensin receptor. LAD: left anterior descending coronary artery. ↑indicates induction or promotion. ↓indicates inhibition or prevention.

Please cite this article as: L. Lu, et al., Apelin/APJ system: A bifunctional target for cardiac hypertrophy, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.11.215

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6.3. Hypertension Hypertension is a progressive vascular syndrome characterised by a continuous increase in arterial blood pressure [58]. It is responsible for cardiac hypertrophy by increasing the burden of the heart. Moreover, blood pressure-lowering therapy (angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist) has been shown to reduce the degree of cardiac hypertrophy significantly [59,60]. Recent studies investigate that apelin/APJ participates in the process of hypertension associated cardiac hypertrophy. Plasma apelin decreases in patients with hypertension compared with healthy subjects [59,61]. Intraperitoneally administered apelin reduces blood pressure in hypertensive rats by inhibiting renin–angiotensin system [62]. Angiotensin-converting enzyme 2 (ACE2) can metabolise Ang II to generate the beneficial heptapeptide Ang-(1–7), which serves as an anti-cardiac hypertrophy factor [63–65]. Apelin can enhance the level of ACE2 in the failing hearts [66]. These results hint that apelin may activate the ACE2/ Ang-(1–7) axis to alleviate cardiac hypertrophy. (Table 1). However,there are some contradictory reports about the effects of apelin/APJ on hypertension. Apelin gene transfer into the rostral ventrolateral medulla induces chronic blood pressure elevation in normotensive rats [37]. In addition, chronic infusion of apelin-13 into the paraventricular nucleus induces hypertension through increasing the levels of plasma norepinephrine and arginine vasopressin in normotensive rats [38]. Gomolka et al. revealed that centrally administered apelin induced a significant increase of blood pressure in normotensive rats under resting conditions [67]. Thus, apelin can induce hypotensive or hypertensive effects depending on the site of apelin injection (peripheral action that would be beneficial and a deleterious action of apelin once injected in the central nervous system). 6.4. Myocarditis Myocarditis, which contributes to cardiac damage, is an inflammatory disease of the heart caused by bacteria, viruses, autoimmune diseases and other factors [68]. It has been reported that eosinophilic myocarditis is an unusual cause of left ventricular hypertrophy [69]. TNF-α, a proinflammatory cytokine, can induce cardiac hypertrophy as well [19]. Therefore, myocarditis may be associated with cardiac hypertrophy. TLR4 belongs to the family of Toll-like receptors and is capable of recognizing lipopolysaccharide, a cell wall component of gram-negative bacteria that initiates inflammatory response in mammals [70]. Dange et al. verified that central blockade of TLR4 attenuated hypertension, myocardial inflammation and cardiac hypertrophy in Ang II-infused rats [60]. Therefore, these findings support the theory that myocarditis may trigger cardiac hypertrophy. Recent studies indicate that apelin is related to inflammation, which contributes to myocarditis and cardiac hypertrophy. LPS, IL-6, or interferon-α treatment enhances the levels of enteric apelin in rodents [71]. Chen et al. found that apelin activated the expression of some inflammatory cytokines including TNF-α, IL-1β, IL-10, MIP-1α and MCP1 in BV2 cells via PI3K/Akt and MEK/Erk pathways [72]. However, the knockdown of apelin is associated with significantly increased IL-1βinduced release of IL-6 and IL-8 in primary amnion cells, which indicates that apelin has anti-inflammatory effects in human pregnancy [73]. Apelin attenuates pulmonary inflammation in rat pups [74]. According to these results, we can assume that apelin may play an inverse role in inflammation of various tissues. (Table 1). 6.5. Myocardial infarction Myocardial infarction (MI) is a major cause of heart failure, with progressive worsening of cardiac performance due to structural and functional alterations [40]. Ellis et al. clarified that cardiac hypertrophy was frequent in patients with coronary occlusion or myocardial infarction [75]. A large number of evidence indicates that apelin ameliorates

myocardial infarction. [Pyr1]-apelin-13 markedly prevents myocardial damage through reducing oxidative injury and enhancing NO production in a rat model of MI [76]. In addition, apelin-12 also limits the myocardial infarction size in experimental rats [77]. Li et al. demonstrated that the ratio of HW/BW, the levels of β-MHC and ANP were markedly elevated in mice 14 days post-MI compared with sham control mice. Treating post-MI mice with apelin-13 leads to a significant decrease in the ratio of HW/BW and suppresses the expression of β-MHC and ANP in mice 14 days post-MI [40]. Hou et al. confirmed that apelin had a pivotal role for cardiac protection via up-regulating the expression of Sirt3 in post-MI mice. Sirt3, a member of a highly conserved family of protein deacetylases, plays a potent part in improving cardiac metabolism and in limiting cardiac fibrosis and cardiac hypertrophy [78]. Moreover, myocardial injection of apelin-overexpressing bone marrow cells ameliorates cardiac repair via up-regulating Sirt3 in post-MI mice [79]. These findings indicate that apelin may show a beneficial influence on the development of cardiac hypertrophy promoted by myocardial infarction. (Table 1). 7. APJ acts as a bifunctional receptor in cardiac hypertrophy Scimia et al. elaborated that APJ was essential for the protective effects of apelin on cardiac hypertrophy. Furthermore, APJ acts as a bifunctional receptor in cardiac hypertrophy. Freshly isolated APJ-null cardiomyocytes exhibited an attenuated response to stretch, which means that APJ is also a mechanosensor. The activation of APJ by stretch increased cardiomyocyte cell size and induced molecular markers of cardiac hypertrophy, which can be prevented by knock down of βarrestin. Therefore, stretch signals activating APJ are mediated via βarrestin resulting in detrimental cardiac hypertrophy [17]. In summary, APJ can translate different chemical (apelin) and mechanical (stretch) signals into opposite phenotypical behavior, which may be explained by different molecular responses. Moreover, our laboratory confirmed that static pressure elevated the diameter, volume and protein content of H9c2 cardiomyocytes. APJ shRNA blocked static pressure induced-cardiomyocyte hypertrophy. The levels of PI3K and Akt phosphorylation, LC3-II/I and beclin-1 (markers of autophagy) were also elevated in static pressurestimulated cells. We pre-incubated cells with the specific inhibitors of PI3K and Akt, autophagy and hypertrophy of cardiomyocytes induced by static pressure were significantly blocked. Therefore, we demonstrated that APJ, a static pressure sensitive receptor, was able to promote H9c2 cardiomyocyte hypertrophy via PI3K-autophagy pathway [14]. In addition, it has been explored that the laminar shear stress has some influences on the expression of apelin/APJ in human endothelial cells [80]. Thus, many kinds of mechanical force are able to affect the apelin/APJ system, including stretch and static pressure. 8. The expression of apelin/APJ in cardiac hypertrophy Stretch causes cardiac hypertrophy. However, the concentration of apelin remains unchanged in stretched and non-stretched cardiomyocytes [17]. Plasma apelin levels in left ventricular hypertrophy (LVH) show no change compared with control rats [24]. Serum apelin levels are significantly lower in hypertensive patients with LVH compared with those without LVH [23]. Falcao-Pires et al. discovered that apelin plasma levels and apelin/APJ myocardial expression had no significant difference in patients with mitral stenosis, aortic stenosis and aortic stenosis plus diabetes. Regarding to rats, apelin plasma levels increased in left ventricular hypertrophy while the myocardial expression of apelin/APJ decreased. Considering the positive inotropic and vasodilator properties of apelin, the elevation in plasma levels of apelin may represent a compensatory mechanism to maintain myocardial function [81]. In terms of this noteworthy phenomenon, we are supposed to measure the expression of apelin/APJ in different heart chambers, especially in the left

Please cite this article as: L. Lu, et al., Apelin/APJ system: A bifunctional target for cardiac hypertrophy, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.11.215

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ventricle, to describe the accurate relationship between apelin and left ventricle hypertrophy. Moreover, we need to collect more clinical data to show the changes of apelin/APJ in subjects with or without cardiac hypertrophy. Furthermore, they illustrated that apelin plasma levels correlated positively with left ventricle mass index both in humans and in rats [81]. Therefore, Not only does apelin/ APJ system play a corroborative role in cardiac hypertrophy, but circulating apelin levels may also assess whether patients have cardiac hypertrophy or not. Moreover, apelin plasma levels are likely to reflect the severity of cardiac hypertrophy in clinical. 9. Conclusion and prospection APJ acts as a dual receptor in cardiac hypertrophy. Apelin activates APJ through Gai protein, which exerts beneficial effects on cardiac hypertrophy. However, stretch stimulates APJ via recruiting β-arrestin, which plays detrimental roles in cardiac hypertrophy. Selectively activating Gprotein pathway or blocking β-arrestin signals may represent a useful pharmacological therapy for the treatment of cardiac hypertrophy. Chen et al. revealed that serine 348 of the C-terminal portion of APJ was the key phosphorylation site for APJ interactions with β-arrestin1/2. Serine 348 mutation of APJ resulted in β-arrestin inactive with no impact on the binding of Gαi protein. Accordingly, the mutagenesis of serine 348 maked APJ a biased receptor activating G-protein pathways to elicit a protective response except for the recruitment of β-arrestin [82]. Brame et al. identified MM07 as a biased agonist for APJ. It activated APJ preferentially via stimulating G-protein pathways but avoids activating β-arrestin–dependent pathways. MM07 improved drug efficacy by selectively stimulating vasodilatation and inotropic actions, which means MM07 may ameliorate cardiac hypertrophy in the clinic [83]. Overall, apelin/APJ shows a distinct role in cardiac hypertrophy. Not only can apelin/APJ blunt the progression of cardiac hypertrophy, but apelin/APJ is also quite likely to induce cardiac hypertrophy. Thus, apelin/APJ is quite likely to act as a double-edged sword in the occurrence and the development of cardiac hypertrophy. As for the reason for this discrepancy, firstly, central administration of apelin induces cardiac hypertrophy. However, peripheral administration of apelin plays opposite roles in cardiac hypertrophy depending on whether some risk factors such as Ang II and H2O2 have already existed or not, which means peripheral administration of apelin ameliorates cardiac hypertrophy under pathological conditions. However, it may cause hypertrophy under nonpathological conditions. Secondly, treating the subjects with apelin in different concentration (non-physiological 500–2000 nM vs physiological 1–100 nM) or for different time periods (short-term or long-term) may bring about inconsistent results. Finally, APJ integrates apelin and stretch stimuli, biasing the levels of G-protein signals versus β-arrestin recruitment accordingly. This phenomenon hints that apelin/APJ may activate different downstream signals to cause inverse effects on cardiac hypertrophy. Even though cardiac hypertrophy is a serious disease, therapeutic measures of cardiac hypertrophy should ideally impair neither the normal post-natal growth of hearts nor its adequate growth in response to exercise. It would be of great therapeutic necessity to prevent pathological cardiac hypertrophy. However, such prevention requires an appropriate balance between inhibition of maladaptive pathological hypertrophy and preservation of adaptive physiological hypertrophy. Taken together, in order to ameliorate the pathological cardiac hypertrophy, future studies will be expected to deliberately define the precise relationship between the apelin/APJ system and pathological cardiac hypertrophy. However, the clinical usage of apelin in the treatment of cardiac hypertrophy is restrained because of its remarkably short half-life in body circulation. Serpooshan et al. applied a nanocarrier try to overcome this kind of defect. They utilized a special drug delivery system consisting of polyethylene glycol (PEG)-conjugated liposomal nanoparticles as an efficient delivery approach for [Pyr1]-apelin-13 in a TAC mouse model. As a consequence, the novel administration of [Pyr1]-apelin-13 nanocarriers

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markedly alleviated left ventricular hypertrophy and pressure overloadinduced cardiac dysfunction [84]. Hence, this kind of drug delivery system is likely to show an unprecedented efficacy to treat cardiac hypertrophy. With respect to the clinical use of apelin, we ought to work out the most optimal dosage and the most efficient administration method in the near future. Conflict of interest statement The authors report no relationships that could be construed as a conflict of interest. Acknowledgements This work was supported by the grants from the National Natural Science Foundation of China (81270420, 81470434, 81503074), the Construct Program of the Key Discipline in Hunan Province, the China Postdoctoral Science Foundation (2014M560647 and 2015T80875), Hunan Provincial Science and Technology Project (2015RS4040), Administration of Traditional Chinese Medicine of Hunan Province (201578), Health and Family planning commission of Hunan Province (B2015-48) and Zhengxiang Scholar Program of University of South China (2014-004). Reference [1] B.F. O'Dowd, M. Heiber, A. Chan, H.H. Heng, L.C. Tsui, J.L. Kennedy, et al., A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11, Gene 136 (1993) 355–360. [2] K. Tatemoto, M. Hosoya, Y. Habata, R. Fujii, T. Kakegawa, M.X. Zou, et al., Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor, Biochem. Biophys. Res. Commun. 251 (1998) 471–476. [3] C. Chaves-Almagro, I. Castan-Laurell, C. Dray, C. Knauf, P. Valet, B. Masri, Apelin receptors: from signaling to antidiabetic strategy, Eur. J. Pharmacol. 763 (2015) 149–159. [4] K. Shin, A. Pandey, X.Q. Liu, Y. Anini, J.K. Rainey, Preferential apelin-13 production by the proprotein convertase PCSK3 is implicated in obesity, FEBS Open Bio. 3 (2013) 328–333. [5] Y. Habata, R. Fujii, M. Hosoya, S. Fukusumi, Y. Kawamata, S. Hinuma, et al., Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum, Biochim. Biophys. Acta 1452 (1999) 25–35. [6] A. Kasai, Y. Ishimaru, T. Kinjo, T. Satooka, N. Matsumoto, Y. Yoshioka, et al., Apelin is a crucial factor for hypoxia-induced retinal angiogenesis, Arterioscler. Thromb. Vasc. Biol. 30 (2010) 2182–2187. [7] S.Y. Lv, Y.J. Yang, Q. Chen, Regulation of feeding behavior, gastrointestinal function and fluid homeostasis by apelin, Peptides 44 (2013) 87–92. [8] C. Bertrand, P. Valet, I. Castan-Laurell, Apelin and energy metabolism, Front. Physiol. 6 (2015) 115. [9] C. Knauf, A. Drougard, A. Fournel, T. Duparc, P. Valet, Hypothalamic actions of apelin on energy metabolism: new insight on glucose homeostasis and metabolic disorders, Hormo. Metab. Res. 45 (2013) 928–934 (= Hormon- und Stoffwechselforschung = Hormones et metabolisme). [10] G.D. Barnes, S. Alam, G. Carter, C.M. Pedersen, K.M. Lee, T.J. Hubbard, et al., Sustained cardiovascular actions of APJ agonism during renin-angiotensin system activation and in patients with heart failure, Circ. Heart Fail. 6 (2013) 482–491. [11] J. Cao, H. Li, L. Chen, Targeting drugs to APJ receptor: the prospect of treatment of hypertension and other cardiovascular diseases, Curr. Drug Targets 16 (2015) 148–155. [12] D. Wu, L. He, L. Chen, Apelin/APJ system: a promising therapy target for hypertension, Mol. Biol. Rep. 41 (2014) 6691–6703. [13] C. Foussal, O. Lairez, D. Calise, A. Pathak, C. Guilbeau-Frugier, P. Valet, et al., Activation of catalase by apelin prevents oxidative stress-linked cardiac hypertrophy, FEBS Lett. 584 (2010) 2363–2370. [14] F. Xie, W. Liu, F. Feng, X. Li, L. Yang, D. Lv, et al., A static pressure sensitive receptor APJ promote H9c2 cardiomyocyte hypertrophy via PI3K-autophagy pathway, Acta Biochim. Biophys. Sin. 46 (2014) 699–708. [15] F. Xie, W. Liu, F. Feng, X. Li, L. He, D. Lv, et al., Apelin-13 promotes cardiomyocyte hypertrophy via PI3K-Akt-ERK1/2-p70S6K and PI3K-induced autophagy, Acta Biochim. Biophys. Sin. 47 (2015) 969–980. [16] A.F. Ceylan-Isik, M.R. Kandadi, X. Xu, Y. Hua, A.J. Chicco, J. Ren, et al., Apelin administration ameliorates high fat diet-induced cardiac hypertrophy and contractile dysfunction, J. Mol. Cell. Cardiol. 63 (2013) 4–13. [17] M.C. Scimia, C. Hurtado, S. Ray, S. Metzler, K. Wei, J. Wang, et al., APJ acts as a dual receptor in cardiac hypertrophy, Nature 488 (2012) 394–398. [18] S. Wu, J. Gao, C. Ohlemeyer, D. Roos, H. Niessen, E. Kottgen, et al., Activation of AP-1 through reactive oxygen species by angiotensin II in rat cardiomyocytes, Free Radic. Biol. Med. 39 (2005) 1601–1610.

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Please cite this article as: L. Lu, et al., Apelin/APJ system: A bifunctional target for cardiac hypertrophy, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.11.215