Apelin/APJ System: A Novel Therapeutic Target for Myocardial Ischemia/Reperfusion Injury

Abstract

Apelin is the endogenous ligand of the G protein-coupled receptor, APJ. Recently, researches indicate that the apelin/APJ system involves in myocardial ischemia–reperfusion injury (MIRI), which is a common pathophysiological process in patients with heart diseases and therapies. The reperfusion induces the expression of apelin and APJ receptor, which play an important role in cardioprotection of MIRI. The apelin/APJ system alleviates MIRI mainly by decreasing mitochondrial reactive oxygen species and delaying the opening of mitochondrial permeability transition pores, which induce the initiation of mitophagy. Besides, the apelin/APJ system prevents mitochondrial oxygen damage and lipid peroxidation through nitric oxide formation. The apelin/APJ system also improves MIRI through other pathways, including promoting metabolic and functional recovery, significantly increasing myocardial capillary density and arteriole formation, inhibiting endoplasmic reticulum stress-induced cell apoptosis, and maintaining integrity of cell membranes. In this review, we discuss how the mechanisms of the apelin/APJ system reverse MIRI in detail and elaborate on APJ agonists, which may be used for therapy of MIRI.

Introduction

APJ, first identified through homology cloning in 1993, is a seven-transmembrane G protein-coupled receptor (O'Dowd et al., 1993). Apelin is an endogenous ligand of APJ, isolated from bovine stomach tissue in 1998 (Tatemoto et al., 1998). Apelin and its receptor APJ are widely expressed in various tissues, including small brain, hypothalamus, endotheliocyte, heart, lung, kidney, and vessels, especially in the cardiovascular system (Lv et al., 2013). The apelin/APJ system exerts important physiological and pathological effects, such as adjusting blood pressure, systolic function of heart, immunity, glucose homeostasis, as well as cell proliferation, and angiogenesis. Our research group investigates the role of the apelin/APJ system in the cardiovascular system and lung cancer. We report that apelin-13 stimulates vascular smooth muscle cell proliferation through pERK1/2-cyclin D1 signal cascade (Li et al., 2008). The static pressure upregulates expression of APJ and promotes cardiomyocyte hypertrophy by a PI3K-autophagy pathway (Xie et al., 2014). Apelin-13 promotes lung adenocarcinoma cell migration through PAK1-cofilin phosphorylation (Lv et al., 2016). It also promotes lung adenocarcinoma cell proliferation through ERK1/2 signaling-induced autophagy (Yang et al., 2014).

The preproapelin consists of 77 amino acid residues and is cleaved into shorter biologically active C-terminal fragments, including apelin-12, -13, -17, and -36 (Kawamata et al., 2001). Apelin-12 is the minimal fragment that possesses a high affinity for the APJ receptor and cardioprotective features, including increasing of myocardial contractility, reducing of mean arterial pressure, and limiting of myocardial infarction. Apelin-13, which is the most widely studied, inhibits apoptosis after ischemia/reperfusion injury in cerebral, heart, and renal systems. Apelin-17 regulates cardiac conduction and excitability. Apelin-36 reduces cerebral infarct volume and protects against brain and heart ischemic injury.

Myocardial reperfusion is the most fundamental treatment for myocardial infarction, which causes myocardial injury (Jennings et al., 1995). One of the major mechanisms is excessive oxygen-free radical, which attacks the blood-supplying organization and leads to structural damage and functional or metabolic disorder. Beside, inadequate resynthesis of ATP, loss of membrane phospholipids, and intracellular calcium overload also contribute to myocardial ischemia–reperfusion injury (MIRI) (Ladilov et al., 2003; Kutala et al., 2007). Furthermore, oxidative stress and calcium overload can induce the abrupt opening of the mitochondrial permeability transition pores (MPTPs) during MIRI (Ruiz-Meana et al., 2007), whereas the abrupt opening of MPTPs causes mitochondrial swelling and uncoupling of oxidative phosphorylation, which result in myocardial cell necrosis and apoptosis (Shanmuganathan et al., 2005). The common pathophysiological characteristics of MIRI are myocardial cell apoptosis (Althaus et al., 1977), reperfusion arrhythmia, (Manning and Hearse, 1984), myocardial stunning (Bolli and Marban, 1999), infarct size (IS) enlargement, (Entman et al., 1991), and microvascular obstruction and intramyocardial hemorrhage (Krug et al., 1966).

Recent studies indicate that the apelin/APJ system plays an important role in MIRI. The apelin/APJ system alleviates MIRI mainly by potentially decreasing mitophagy, increasing nitric oxide (NO) formation, promoting angiogenesis, attenuating endoplasmic reticulum (ER) stress, enhancing cell membrane integrity, and maintaining the Ca²⁺ transient. In this article, we review the beneficial effects and mechanisms of the apelin/APJ system on MIRI. Furthermore, we elaborate the structure, feature, and function of natural apelin peptides and synthetic APJ agonists.

Protection Roles of the Apelin/APJ System on Myocardial Ischemia–Reperfusion Injury

A series of evidences strongly suggest that the apelin/APJ system protects the heart against MIRI. We describe that apelin-12, -13, and -36 ameliorate MIRI (Table 1). Furthermore, we illustrate the protection effects of various subtypes of apelin.

Table 1.

The Apelin/APJ System Protects the Heart Against Myocardial Ischemia–Reperfusion Injury

Apelin	Experiment model	Role	Mechanisms	References
Apelin-12	In vivo
	Rat LAD occlusion 40-min reperfusion	Decrease IS/AAR	Cu, Zn, SOD,CAT	Pisarenko et al. (2014)
	Rat LAD occlusion 60-min reperfusion	Limit IS	NO	Pisarenko et al. (2012a)
	Rat LAD occlusion 40-min reperfusion	Decrease IS/AAR	NO, Mito-KATP	Pisarenko et al. (2015b)
	In vitro
	Langendorff reperfusion rat heart	Increase LVDP × HR	Cu, Zn, SOD,CAT	Pisarenko et al. (2014)
	Langendorff reperfusion rat heart	Enhance LVDP × HR	ROS	Pisarenko et al. (2015c)
	Rat ventricular myocardial H9C2 cells	Decrease H9C2 cell apoptosis	ROS	Pisarenko et al. (2015c)
	Langendorff reperfusion rat heart	Decrease H9C2 cell apoptosis	NO, Mito-KATP	Pisarenko et al. (2015b)
Apelin-13	In vivo
	Mouse LAD ligation 30-min reperfusion	Decrease IS	MPTP	Simpkin et al. (2007)
	Rat LCA occlusion 30-min reperfusion	Inhibit cardiac cell apoptosis	ER stress	Tao et al. (2011)
	Mouse LAD ligation	Increase myocardial progenitor cells	SDF-1-/CXCR-4	Li et al. (2012)
	Rat LCA ischemia 30-min reperfusion	Decrease IS/AAR	GSK-3β-MPTP	Yang et al. (2015)
	In vitro
	Langendorff reperfusion mouse heart	Decrease IS	MPTP	Simpkin et al. (2007)
	Langendorff reperfusion rat heart	Reduce IS	NO	Rastaldo et al. (2011)
	Langendorff reperfusion rat heart	Decrease coronary perfuse pressure	SOD	Zeng et al. (2009)
	In myocardial cells	Inhibit cell apoptosis	SOD	Zeng et al. (2009)
	Langendorff reperfusion rat heart	Improve LVDP recovery	SR	Wang et al. (2013b)
	In myocardial cells	Decrease cell apoptosis	MPTP	Yang et al. (2015)
Apelin-36	In vivo
	Mouse LAD ligation 30-min reperfusion	Limit IS	MPTP	Simpkin et al. (2007)
	In vitro
	Langendorff reperfusion mouse heart	Limit IS	MPTP	Simpkin et al. (2007)

AAR, myocardial nonischemic area from the area at risk; CAT, catalase; GSK-3β, glycogen synthase kinase-3β; IS, infarct size; LAD, the left anterior descending coronary artery; LCA, the left coronary artery; LVDP × HR, the left ventricular developed pressure and heart rate; Mito-KATP, ATP-dependent K⁺ channels; ROS, reactive oxygen species; SOD, superoxide dismutase; SR, sarcoplasmic reticulum; MPTP, mitochondrial permeability transition pore; mito-KATP, mitochondrial ATP-dependent K⁺ channels.

Apelin-12 significantly decreases the percent ratio of IS and increases energy recovery of postischemic cardiomyocytes in in vivo model of MIRI (Pisarenko et al., 2013, 2015a). Apelin-12 also can upregulate cardiac antioxidant systems and reduce lipid peroxidation by increasing the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase. Similarly, apelin-12 also limits IS and reduces cardiomyocyte membrane damage by enhancement of NO formation in MIRI (Pisarenko et al., 2012a). Besides, cardioprotection with apelin-12 is mediated by signaling through PLC and survival kinases, PKC, PI3K, and MEK1/2, with activation of downstream targets, NO synthase (NOS), and mito KATP channels (Pisarenko et al., 2015b).

Zeng et al. (2009) find that the administration of apelin-13 can induce phosphorylation of ERK1/2 and AKT, enhance the expression of eNOS, and eventually ameliorate MIRI. Meanwhile, apelin-13 completely abolishes ER stress-induced apoptosis through PI3K/AKT, AMPK, and ERK in MIRI (Tao et al., 2011). Apelin-13 also limits IS (Rastaldo et al., 2011) and diminishes postischemic myocardial contracture by enhancement of NO formation in MIRI (Azizi et al., 2013). Apelin-13 reduces MIRI by recovering sarcoplasmic reticulum (SR) function (Wang et al., 2013b). Apelin-13 reduces the decline in mitochondrial membrane potential and protects the heart through the PI3K/AKT-GSK-3β-MPTP pathway in MIRI (Yang et al., 2015). Besides, apelin-13 increases progenitor cells (PCs) and angiogenesis through SDF-1-/CXCR-4 in mice after LAD ligation (Li et al., 2012; Wang et al., 2013a).

Apelin-36 reduces IS and produces direct cardioprotective actions through delaying of MPTPs involving the PI3K-Akt signal pathway in MIRI (Simpkin et al., 2007). Overall, apelin-12, apelin-13, and apelin-36 play protection roles in MIRI.

Protection Mechanisms of the Apelin/APJ System on Myocardial Ischemia–Reperfusion Injury

Apelin/APJ system potentially decreases mitophagy

Selective autophagy of mitochondria (mitophagy) refers to the phenomenon that damaged mitochondria are degraded by the lysosome-dependent autophagy pathway (Kim and Lemasters, 2011). Oxidative stress, the abrupt opening of MPTPs, and damaged organelles are important triggers of cell mitophagy. Some studies demonstrate that excessive activation of autophagy can lead to autophagic cell death and left ventricular dysfunction in MIRI (Matsui et al., 2007). Likewise, downregulation of autophagy decreases the number of apoptotic cardiomyocytes in MIRI (Ke et al., 2015). Yu et al. (2015) find that damaged mitochondria and missing of myofilaments are contained within autophagosome in MIRI. Moreover, inhibition of mitophagy can ameliorate mitochondrial impairment and protect the heart against MIRI by PI3K/Akt/mTOR signaling. Furthermore, Ji et al. (2016) reveal that myocardial IS and apoptosis are ameliorated by elimination of reactive oxygen species (ROS) and suppression of PINK1/Parkin-dependent mitophagy after MIRI. Therefore, those results indicate that mitophagy, which surely occurs in MIRI, leads to apoptosis and heart dysfunction in MIRI. In addition, inhibition of mitophagy can protect the heart against MIRI.

The apelin/APJ system plays an important role of inhibiting the abrupt opening of MPTPs in MIRI. The balance of mitophagy is essential to mitochondrial integrity and efficiency (Lemasters, 2014). During mitophagy, mitochondria damage, depolarize, uncouple, and undergo large amplitude swelling due to opening of MPTPs. In addition, the abrupt opening of MPTPs initiates the process of mitophagy (Rodriguez-Enriquez et al., 2004; Soskic et al., 2008) and induces the development of apoptosis (Lemasters et al., 1998; Ke et al., 2015). Inversely, inhibition of abrupt opening of MPTPs stabilizes mitochondria and prevents myocardial apoptosis in MIRI (Shanmuganathan et al., 2005). Yang et al. (2015) find that apelin-13 reduces the decline in mitochondrial membrane potential and inhibits the opening of MPTPs by PI3K/AKT/GSK-3β. Simpkin et al. (2007) also indicate that administration of apelin-13 and 36 at reperfusion delays MPTP opening ratios and results in direct cardioprotective actions through PI3K-Akt, p44/42 in MIRI. Besides, activation of PI3K/AKT inhibits the abrupt opening of MPTPs and ameliorates MIRI (Rahman, 2010). Thus, the apelin/APJ system might decrease mitophagy by inhibiting MPTP opening through PI3K/AKT in MIRI.

The apelin/APJ system inhibits generation of mitochondrial ROS, which leads to the abrupt opening of MPTPs and cell death in response to MIRI (Schriewer et al., 2013). Apelin-12 and apelin-13 selectively inhibit mitochondrial ROS generation and improve heart functional and metabolic recovery after MIRI (Pisarenko et al., 2015c). Mottaghi et al. (2012) also report that apelin-13 decreases ROS overproduction and oxidative stress-induced apoptosis by PI3K/AKT and MAPK/ERK1/2 signaling pathways under hypoxia preconditioning. Similarly, apelin-12 and its structural analog lessen oxidative stress by increasing antioxidant enzyme activation and reducing ROS formation in MIRI (Pisarenko et al., 2014).

Besides, Lu et al. (2011) identify that the PI3K/Akt signaling pathway inhibits ROS generation and modulates MPTP opening in MIRI. However, Hausenloy et al. (2010) show that mitochondrial ROS induces and phosphorylates AKT in MIRI. Those conflicting results are mainly due to their different processing time and pH value of culture environment to cardiomyocytes. Lu et al. culture cardiomyocytes at pH 6.2 and the cultured cardiomyocytes are exposed to ischemia for 2 h, followed by reperfusion for 1 h. However, Schriewer et al. culture cardiomyocytes at pH 7.2 and the cultured cardiomyocytes are handled with ischemia for 10 min, followed by reperfusion for 10 min.

The apelin/APJ system potentially decreases mitophagy. Although it is not direct, evidence suggests that the apelin/APJ system ameliorates MIRI through inhibition of mitophagy. Relationship between activation of the apelin/APJ system and attenuation of mitophagy still needs further research. It is reported that the apelin/APJ system inhibits ROS generation and delays MPTP opening. However, both ROS and MPTP opening contribute to the occurrence of mitophagy. In this study, ROS and MPTPs can be a bridge that connects the apelin/APJ system and mitophagy. Finally, we drew a summary that the apelin/APJ system potentially decreases mitophagy by inhibiting mitochondrial ROS and MPTP opening. (Fig. 1).

FIG. 1.

Apelin/APJ alleviates MIRI by potentially decreasing mitophagy and inhibiting ER stress. Both ROS and MPTP opening contribute to the occurrence of mitophagy. The mitophagy or ER stress induces cell apoptosis in MIRI. Apelin/APJ system activates the PI3K/AKT signal pathway, resulting in attenuation of mitochondrial ROS production and increase of NO formation. The NO-induced mito-KATP opener can inhibit the abrupt opening of MPTPs. Besides, the NO also disperses the ROS. Besides, the apelin/APJ system inhibits MPTPs by the PI3K/AKT/GSK-3β signal pathway. The apelin/APJ system also inhibits ER stress-induced cell apoptosis through PI3K/AKT, AMPK, and ERK signal pathways. ER, endoplasmic reticulum; MIRI, myocardial ischemia–reperfusion injury; mito-KATP, mitochondrial ATP-dependent K⁺ channels; MPTP, mitochondrial permeability transition pore; NO, nitric oxide; ROS, reactive oxygen species.

Apelin/APJ system increases NO formation and promotes recovery of energy metabolism

NO, which is a potent vasodilator and antioxidant, provides consistent cytoprotection and reduces infarction volume in MIRI. Nitrite reduction to NO may be catalyzed by myoglobin, hemoglobin, or other metal-containing enzymes and occurs at increasing rates under conditions of physiologic hypoxia or ischemia (Dezfulian et al., 2007). Exogenous administration of NO prior can prevent mitochondrial oxygen damage and protect the myocardium against MIRI (Schulz et al., 2004). In addition, the endothelial cell-induced NO formation can delay the opening of MPTPs and enhance cardioprotection in hypoxia and reoxygenation injury (Leucker et al., 2011).

Zeng et al. (2009) demonstrate that the apelin/APJ system increases NO formation and improves MIRI-induced cardiac dysfunction. The apelin/APJ system promotes NOS activation mainly through enhancing the phosphorylation of AKT. Apelin-12 activates eNOS and induces cardioprotection by PI3K/AKT after reperfusion (Pisarenko et al., 2013). Pisarenko et al. (2012a) also reveal that apelin-12 can reduce cardiomyocyte membrane damage and limit IS in MIRI through increasing NO formation. In Langendorff-perfused rat hearts, strong inhibition of eNOS decreases NO formation and further exacerbates MIRI (Kobara et al., 2003). Consistently, Rastaldo et al. (2011) describe that inhibition of NO formation abolishes or weakens protection role of apelin-13 and apelin-12 in MIRI. Above all, the apelin/APJ system increases NO formation and protects the heart against MIRI.

Furthermore, NO formation is involved in the process of recovery of energy metabolism induced by the apelin/APJ system. Restoration of energy metabolism increases functional recovery of the heart and decreases cell membrane damage in MIRI. The preischemic infusion of apelin-12 can markedly increase myocardial ATP content and decrease AMP accumulation at the end of reperfusion (Pisarenko et al., 2010). Administration of the NOS inhibitor can profoundly abolish the influence of apelin-12 on energy metabolic and functional recovery of reperfused hearts (Pisarenko et al., 2012b). Thus, NO formation participates in the ameliorating process of apelin-12 in MIRI through the recovery of energy metabolism. Additionally, the mitochondrial ATP-dependent K⁺ channel (mito-KATP) opener inhibits the abrupt opening of MPTPs (Akopova et al., 2014). Apelin-12 induces cardioprotection through mito-KATP channels and NO formation through PLC, PKC, PI3K, and MEK1/2 in isolated perfused working rat heart (Pisarenko et al., 2015b). The apelin/APJ system may inhibit MPTP opening by NO-induced KATP opener through PI3K/AKT (Fig. 1).

Apelin/APJ system promotes angiogenesis and recovery of coronary flow

Myocardial angiogenesis improves heart function by increasing the capillary/arteriolar density in myocardial infarction (Sasaki et al., 2002). The apelin/APJ system plays an important role in angiogenesis (Kunduzova et al., 2008). Apelin-13 induces vascular smooth cell proliferation through ERK-dependent activation of jagged-1/Notch3 (Li et al., 2013) and PI3K/AKT signaling pathways (Liu et al., 2010). Apelin-13 also promotes capillary density through overexpression of the proangiogenic factor, VEGF, in MIRI (Azizi et al., 2015). Furthermore, Li L et al. (2012) indicate that treatment with apelin-13 significantly increases myocardial capillary density and arteriole formation, then improves cardiac repair by the homing of vascular PCs through SDF-1-/CXCR-4 signaling. Consistently, the deficiency of apelin decreases vascular sprouting and compromises in vivo myocardial angiogenesis (Wang et al., 2013a). Pisarenko et al. (2012b) reveal that apelin-12 improves recovery of coronary flow and heart function by enhancing myocardial ATP in MIRI. These observations suggest that the apelin/APJ system induces cardioprotection through promoting of myocardial angiogenesis and recovery of coronary flow in MIRI.

Apelin/APJ system attenuates ER stress

The ER is responsible for protein synthesis, folding, maturation, and transport. ER stress not only gives rise to the accumulation of unfolded or misfolded proteins in the ER (Kaufman, 1999) but also induces cell apoptosis through caspase-12 and JNK (Boyce and Yuan, 2006). Suppression of ER stress can protect the myocardium from MIRI (Liu et al., 2008). In vivo, the administration of apelin-13 induces cardioprotection in MIRI. Furthermore, apelin-13 activates PI3K/Akt, AMPK, and ERK pathways, which are involved in the protection against MIRI through inhibition of ER stress-dependent apoptosis activation (Fig. 1) (Tao et al., 2011). A large number of researches indicate that the apelin/APJ system increases NO formation and protects the heart against MIRI. Moreover, NO formation induces a distinct protective role during the ER stress-induced cell apoptosis (Kitiphongspattana et al., 2007). These results hint that the apelin/APJ system may attenuate ER stress response-induced cell death by promoting NO formation in MIRI. In summary, the apelin/APJ system ameliorates MIRI by inhibiting ER stress.

Apelin/APJ system enhances cell membrane integrity

Cell membrane integrity is essential for cell function. The damage of cell membrane usually leads to increase of permeability and cell edema. Studies indicate that myofibrillar edema and myocyte swelling (Bragadeesh et al., 2008) occurred in MIRI. Damage of cell membrane, which causes dysregulation of Na⁺/Ca²⁺ exchange and Na⁺/H⁺ exchange, is one of the reasons of cell edema. Inhibition of the Na⁺/Ca²⁺ exchange and Na⁺/H⁺ antiport reduces ischemic swelling and improves cardiac viability and functional recovery (Askenasy, 2001).

Lactate dehydrogenase (LDH) leakage is one of the important indices for cell membrane damage of MIRI. The release of LDH at early reperfusion increases by more than twofold compared with the value before ischemia. Apelin-13 enhances cell membrane integrity through inhibiting LDH leakage in MIRI (Zeng et al., 2009). Pisarenko et al. (2015c) investigate that apelin-12 and -13 as well as structural apelin-12 analogs decrease cell membrane damage by better maintaining cell membrane integrity and ion homeostasis (Portman, 2005). Exogenous apelin-12 also significantly decreases LDH leakage and reduces myocardial cell membrane damage by PLC, PKC, PI3K, and MEK1/2 signaling (Pisarenko et al., 2015b). However, inhibition of Na⁺/H⁺ exchange can reverse the effects of apelin-12 on LDH leakage and promote membrane damage in MIRI. Therefore, apelin-12 maintains the integrity of cell membranes through Na⁺/H⁺ exchange. Of course, the integrity of cell membranes also can improve the work of sarcolemmal ion pumps.

Apelin/APJ system maintains Ca²⁺ transient

According to the investigation results of Jeroudi et al. (1994), the perturbations of calcium homeostasis play an important role in reperfusion arrhythmias, including idioventricular rhythm, ventricular tachycardia, and fibrillation after MIRI (Kukreja and Janin, 1997). The inhibition of intracellular Ca²⁺ overload improves the recovery of heart function and prevents the heart from contracture during reperfusion (Chen et al., 1993). The apelin/APJ system has a number of biological effects on calcium modulation. In isolated rat hearts, apelin-13 improves the redox states of SR Ca²⁺ modulators and maintains Ca²⁺ transient in MIRI (Wang et al., 2013b). Maintaining of Ca²⁺ transient can inhibit Ca²⁺ transient and induce cardioprotection in MIRI. Accordingly, the abrupt opening of MPTPs causes strong Ca²⁺ overload and results in hypercontracture of the heart (Ruiz-Meana et al., 2007; Mukherjee et al., 2015). Apelin-13 and apelin-36 inhibit reperfusion-induced hypercontracture of heart by delaying the abrupt opening of MPTPs (Simpkin et al., 2007). Moreover, administration of apelin-16 induces a dose-dependent increase in developed tension, while these positive inotropic effects also can ameliorate cardiac contractility and atrial fibrillation in isolated perfused rat hearts (Szokodi et al., 2002).

Therapeutic Potential of the Apelin/APJ System in Myocardial Ischemia–Reperfusion Injury

Numerous studies indicate that natural peptide apelin-12 ameliorates heart function, including myocardial contractile function, perfusion pressure, and LVEDP in MIRI. However, apelin-12 contains methionine, which is easily oxidized to the corresponding sulfoxide. To increase the chemical stability of apelin-12 and its resistance to aminopeptidase cleavage, Pisarenko et al. (2012c) design three structural analogs of apelin-12, named AI(H-(N(a)Me)Arg–Pro–Arg–Leu–Ser–His–Lys–Gly–Pro–Nle–Pro–Phe–OH), AII(H-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-dAla-OH), and AIII (N^G-Arg(N^GNO₂)-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Phe-NH₂). Furthermore, they observe that both AI and AIII significantly decrease the size of myocardial infarction in in vivo or vitro model of MIRI.

Cyclization can improve peptide potency, such as bioactivity, selectivity, and bioavailability. Hamada et al. (2008) synthesize three cyclic analogs of apelin-12, named cyclic apelin-12 (C1), cyclic apelin-12 (C3), and cyclic apelin-12 (C4). Cyclic apelin-12 (C1) combines amino-terminal with carboxy-terminal. Cyclic apelin-12 (C3) combines amino-terminal with amino acid side chain at position 7. Cyclic apelin-12 (C4) combines amino acid side chain at position 7 with carboxy-terminal. C1, C3, and C4 can activate the intracellular AKT and ERK1/2 signaling pathways, which can directly induce the cardioprotection role in MIRI.

Wang et al. (2013a) design and synthesize two apelin-13 analogs, namely NleInpBrF pyr-1-apelin-13 and NleAibBrF pyr-1-apelin-13. They reveal that these two apelin-13 analogs are resistant to angiotensin-converting enzyme 2 cleavages compared with apelin-13. Furthermore, NleAibBrF pyr-1-apelin-13 markedly mediates cardioprotection through activation of AKT survival pathways and promotion of angiogenesis in MIRI.

Fan et al. (2003) discover that alanine substitutions at the Q1, H7, P12, and F13 positions increase binding of APJ receptor activity and designed three APJ agonists, including apelin-13 Q1A, apelin-13 H7A, and apelin-13 P12A. Moreover, these APJ agonists can blocks HIV-1 entry through the receptor.

Moreover, there are three small-molecule compound targets for APJ receptor. MM07 selectively stimulates G-protein, but avoids activation of detrimental β-arrestin-dependent pathways (Brame et al., 2015). MM07 causes a dose-dependent increase in cardiac output in rats or human volunteers. E339-3D6, a nonpeptidic APJ agonist, is a full agonist with regard to apelin receptor internalization (Iturrioz et al., 2010). E339-3D6 induces vasodilatation of rat aorta prior with noradrenaline and potently inhibits systemic vasopressin release in water-deprived mice. ML233 is the selective small-molecule receptor agonist for APJ. It induces APJ internalization and reduces forskolin and stimulates the increase of intracellular cAMP (Khan et al., 2010).

Overall, synthetic APJ receptor agonists, including apelin-12 analog AI, AIII, and NleAibBrF pyr-1-apelin-13, protect the heart against MIRI (Table 2). These results indicate the probability of production of a drug of new generation for the therapy of MIRI on the basis of these synthetic APJ receptor agonists.

Table 2.

The Role of Natural Apelin Peptides and Synthetic APJ Agonists in Myocardial Ischemia–Reperfusion Injury

Name	Structure	Feature	Model	Form	Role	Reference
Apelin-12	H-RPRLSHKGPMPF-OH	—	In vivo or vitro model of MIRI	Natural peptides	Induce cardioprotection	Pisarenko et al. (2011)
Apelin-12 AI	H-(N^aMe) RPRLSHKGPMPF-OH	Resist cleavage of amino peptidase	In vivo or vitro model of MIRI	Apelin-12 analogs	Induce cardioprotection	Pisarenko et al. (2013)
Apelin-12 AII	HRPRLSHKGPMP-dAla-OH	Resist cleavage of amino peptidase	In vivo or vitro model of MIRI	Apelin-12 analogs	No effect	Pisarenko et al. (2013)
Apelin-12 AIII	N^G-R(N^GNO₂) PRLSHKGPMPF-NH₂	Resist cleavage of amino peptidase	In isolated rat heart model of MIRI	Apelin-12 analogs	Induce cardioprotection	Pisarenko et al. (2015a)
Apelin-12 C1	RPRLSHKGPMPF^b	Improve peptide potency	In PTx-sensitive manner	Apelin-12 analogs	Modulate Akt and ERK1/2 signal pathway	Hamada et al. (2008)
Apelin-12 C3	RPRLSHKGPMPF^b	Improve peptide potency	In PTx-sensitive manner	Apelin-12 analogs	Modulate Akt and ERK1/2 signal pathway	Hamada et al. (2008)
Apelin-12 C4	RPRLSHKGPMPF^b	Improve peptide potency	In PTx-sensitive manner	Apelin-12 analogs	Modulate Akt and ERK1/2 signal pathway	Hamada et al. (2008)
Apelin-13	QRPRLSHKGPMPF	—	In vivo or vitro model of MIRI	Natural peptides	Induce cardioprotection	Simpkin et al. (2007)
Pry-Apelin-13	Pyroglutamate-RPRLSHKGPMPF	—	In vivo rat model of MIRI	Natural peptides	Induce cardioprotection	Azizi et al. (2013)
Apelin-13 A I	NleInpBrF pyr-1-apelin-13	Markedly resist proteolysis of ACE2	In vivo or vitro model of MIRI	Apelin-13 analogs	No effect	Wang et al. (2013a)
Apelin-13 A II	NleAibBrF pyr-1-apelin-13	Markedly resist proteolysis of ACE2	In vivo or vitro model of MIRI	Apelin-13 analogs	Induce cardioprotection and myocardial angiogenesis.	Wang et al. (2013a)
Apelin-13 Q1A	aARPRLSHKGPMPF	Increase binding of APJ receptor activity	In human HEK293 cell	Apelin-13 analogs	Inhibit HIV-1 fusion	Fan et al. (2003)
Apelin-13 H7A	aQRPRLSAKGPMPF	Increase binding of APJ receptor activities	In human HEK293 cell	Apelin-13 analogs	Inhibit HIV-1 fusion	Fan et al. (2003)
Apelin-13P12A	aQRPRLSHKGPMAF	Increase binding of APJ receptor activities	In human HEK293 cell	Apelin-13 analogs	Inhibit HIV-1 fusion	Fan et al. (2003)
Apelin-36	LVQPRQPRSGPGPWQGGRRKFRRQRPRLSHKGPMPF	—	In vivo or vitro model of MIRI	Natural peptides	Reduce IS and produce direct cardioprotective actions	Simpkin et al. (2007)
MM07	cyclo[1-6]CRPRLCHKGPMPF	Preferentially stimulate the G-protein pathway	In rats or human volunteers	Small-molecule compounds	Increase cardiac output	Brame et al. (2015)
ML233	C₁₉H₂₁NO₄S	Selectively activate APJ and against the AT1	In CHOK1 cells	Small-molecule compounds	Reduce intracellular cAMP	Khan et al. (2010)
E339-3D6	C76H98O14 N13S3F3	First nonpeptidic and biased agonist	In isolated rat aorta or water-deprived mice mimice mice	Small-molecule compounds	Induce vasodilatation of rat aorta	Iturrioz et al. (2010)

ACE2, angiotensin-converting enzyme 2; AT1, angiotensin 1 receptor; cAMP, cyclic adenosine monophosphate; PTx, pertussis toxin; ERK1/2, extracellular signal-regulated kinase 1/2; HIV-1, human immunodeficiency virus-1; MIRI, myocardial ischemia–reperfusion injury; ER, endoplasmic reticulum; NO, nitric oxide.

Conclusions

In conclusion, the apelin/APJ system becomes a new protective mechanism and promising therapy target for MIRI. Apelin peptides, including apelin-12, -13, and -36, are beneficial for MIRI. Moreover, the apelin/APJ system produces protective effects on MIRI by potential inhibition of mitophagy, promotion of NO formation and angiogenesis, reduction of ER stress, and maintaining membrane integrity and Ca²⁺ transient. APJ receptor agonists, such as apelin-12 analog AI, AIII, and NleAibBrF pyr-1-apelin-13, induce cardioprotection in MIRI. However, the safety and long-term effect of these agonists still need to be more fully characterized and better defined. Further experimental and clinical studies are needed to determine the potential of therapeutic strategies targeting the APJ receptor in MIRI.

Footnotes

Acknowledgment

This work was supported by grants from the National Natural Science Foundation of China (grant numbers: 81270420, 81470434, 81503074, and 81670265), Zhengxiang Scholar Program of University of South China (2014-004), Hunan Provincial Science and Technology Project (2015RS4040), Administration of Traditional Chinese Medicine of Hunan Province (201578), and Health and Family planning commission of Hunan Province (B2015-48).

Author Disclosure Statement

The authors declare there are no conflicts of interest. This article does not contain any studies with human participants or animals performed by any of the authors.

References

Akopova

O.V.

, Kolchinskaia

L.I.

, Nosar

V.I.

, Buryi

V.A.

, Man'kovskaia

I.N.

, and Sagach

V.F.

(2014). [The effect of ATP-dependent K(+)-channel opener on transmembrane potassium exchange and reactive oxygen species production upon the opening of mitochondrial pore]. Ukr Biochem J, 86, 26–40.

Althaus

, Gurtner

H.P.

, Baur

, Hamburger

, and Roos

(1977). Consequences of myocardial reperfusion following temporary coronary occlusion in pigs; effects on morphologic, biochemical and haemodynamic findings. Eur J Clin Invest, 7, 437–443.

Askenasy

(2001). Is cytotoxic cellular edema real? The effect of calcium ion on water homeostasis in the rat heart. Cardiovasc Toxicol, 1, 21–34.

Azizi

, Faghihi

, Imani

, Roghani

, and Nazari

(2013). Post-infarct treatment with [Pyr1]-apelin-13 reduces myocardial damage through reduction of oxidative injury and nitric oxide enhancement in the rat model of myocardial infarction. Peptides, 46, 76–82.

Azizi

, Faghihi

, Imani

, Roghani

, Zekri

, Mobasheri

M.B.

, et al. (2015). Post-infarct treatment with [Pyr(1)]apelin-13 improves myocardial function by increasing neovascularization and overexpression of angiogenic growth factors in rats. Eur J Pharmacol, 761, 101–108.

Bolli

, and Marban

(1999). Molecular and cellular mechanisms of myocardial stunning. Physiol Rev, 79, 609–634.

Boyce

, and Yuan

(2006). Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ, 13, 363–373.

Bragadeesh

, Jayaweera

A.R.

, Pascotto

, Micari

, Le

D.E.

, Kramer

C.M.

, Epstein

F.H.

, et al. (2008). Post-ischaemic myocardial dysfunction (stunning) results from myofibrillar oedema. Heart, 94, 166–171.

Brame

A.L.

, Maguire

J.J.

, Yang

, Dyson

, Torella

, Cheriyan

, et al. (2015). Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist. Hypertension, 65, 834–840.

10.

Chen

C.C.

, Morishige

, Masuda

, Lin

, Wieland

, Thone

, et al. (1993). R56865, a Na(+)- and Ca(2+)-overload inhibitor, reduces myocardial ischemia-reperfusion injury in blood-perfused rabbit hearts. J Mol Cell Cardiol, 25, 1445–1459.

11.

Dezfulian

, Raat

, Shiva

, and Gladwin

M.T.

(2007). Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics. Cardiovasc Res, 75, 327–338.

12.

Entman

M.L.

, Michael

, Rossen

R.D.

, Dreyer

W.J.

, Anderson

D.C.

, Taylor

A.A.

, Smith

C.W.

, et al. (1991). Inflammation in the course of early myocardial ischemia. FASEB J, 5, 2529–2537.

13.

Fan

, Zhou

, Zhang

, et al. (2003). Structural and functional study of the apelin-13 peptide, an endogenous ligand of the HIV-1 coreceptor, APJ. Biochemistry, 42, 10163–10168.

14.

Hamada

, Kimura

, Ishida

, Kohda

, Morishita

, Ichihara

, et al. (2008). Evaluation of novel cyclic analogues of apelin. Int J Mol Med, 22, 547–552.

15.

Hausenloy

D.J.

, Lim

S.Y.

, Ong

S.G.

, Davidson

S.M.

, and Yellon

D.M.

(2010). Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning. Cardiovasc Res, 88, 67–74.

16.

Iturrioz

, Alvear-Perez

, De Mota

, Franchet

, Guillier

, Leroux

, et al. (2010). Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist. FASEB J, 24, 1506–1517.

17.

Jennings

R.B.

, Steenbergen

Jr , Reimer

K.A.

, and Reimer

K.A.

(1995). Myocardial ischemia and reperfusion. Monogr Pathol, 37, 47–80.

18.

Jeroudi

M.O.

, Hartley

C.J.

, and Bolli

(1994). Myocardial reperfusion injury: role of oxygen radicals and potential therapy with antioxidants. Am J Cardiol, 73, 2B–7B.

19.

, Wei

, Hao

, Xing

, Yuan

, Wang

, et al. (2016). Aldehyde dehydrogenase 2 has cardioprotective effects on myocardial ischaemia/reperfusion injury via suppressing mitophagy. Front Pharmacol, 7, 101.

20.

Kaufman

R.J.

(1999). Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev, 13, 1211–1233.

21.

Kawamata

, Habata

, Fukusumi

, Hosoya

, Fujii

, Hinuma

, et al. (2001). Molecular properties of apelin: tissue distribution and receptor binding. Biochim Biophys Acta, 1538, 162–171.

22.

, Yao

, Li

, Cui

, and Ding

(2015). A2 Adenosine receptor-mediated cardioprotection against reperfusion injury in rat hearts is associated with autophagy downregulation. J Cardiovasc Pharmacol, 66, 25–34.

23.

Khan

, Maloney

P.R.

, Hedrick

, Gosalia

, Milewski

, Li

, et al. (2010). Functional Agonists of the Apelin(APJ) receptor. Probe Reports from the NIH Molecular Libraries Program. (National Center for Biotechnology Information, Bethesda, MD), 2010–2011 Mar 25 [updated 2011 Dec 12], www.ncbi.nlm.nih.gov/books/NBK98921, accessed September 13, 2016 .

24.

Kim

, and Lemasters

J.J.

(2011). Mitochondrial degradation by autophagy (mitophagy) in GFP-LC3 transgenic hepatocytes during nutrient deprivation. Am J Physiol Cell Physiol, 300, C308–C317.

25.

Kitiphongspattana

, Khan

T.A.

, Ishii-Schrade

, Roe

M.W.

, Philipson

L.H.

, and Gaskins

H.R.

(2007). Protective role for nitric oxide during the endoplasmic reticulum stress response in pancreatic beta-cells. Am J Physiol Endocrinol Metab, 292, E1543–E1554.

26.

Kobara

, Tatsumi

, Takeda

, Mano

, Yamanaka

, Shiraishi

, et al. (2003). The dual effects of nitric oxide synthase inhibitors on ischemia-reperfusion injury in rat hearts. Basic Res Cardiol, 98, 319–328.

27.

Krug

, Du Mesnil de

, and Korb

(1966). Blood supply of the myocardium after temporary coronary occlusion. Circ Res, 19, 57–62.

28.

Kukreja

R.C.

, and Janin

(1997). Reperfusion injury: basic concepts and protection strategies. J Thromb Thrombolysis, 4, 7–24.

29.

Kunduzova

, Alet

, Delesque-Touchard

, Millet

, Castan-Laurell

, Muller

, et al. (2008). Apelin/APJ signaling system: a potential link between adipose tissue and endothelial angiogenic processes. FASEB J, 22, 4146–4153.

30.

Kutala

V.K.

, Khan

, Angelos

M.G.

, and Kuppusamy

(2007). Role of oxygen in postischemic myocardial injury. Antioxid Redox Signal, 9, 1193–1206.

31.

Ladilov

, Efe

, Schafer

, Rother

, Kasseckert

, Abdallah

, et al. (2003). Reoxygenation-induced rigor-type contracture. J Mol Cell Cardiol, 35, 1481–1490.

32.

Lemasters

J.J.

(2014). Variants of mitochondrial autophagy: types 1 and 2 mitophagy and micromitophagy (Type 3). Redox Biol, 2, 749–754.

33.

Lemasters

J.J.

, Nieminen

A.L.

, Qian

, Trost

L.C.

, Elmore

S.P.

, Nishimura

, et al. (1998). The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta, 1366, 177–196.

34.

Leucker

T.M.

, Bienengraeber

, Muravyeva

, Baotic

, Weihrauch

, Brzezinska

A.K.

, et al. (2011). Endothelial-cardiomyocyte crosstalk enhances pharmacological cardioprotection. J Mol Cell Cardiol, 51, 803–811.

35.

, Li

, Qin

, Pan

, Feng

, Chen

, et al. (2008). Apelin-induced vascular smooth muscle cell proliferation: the regulation of cyclin D1. Front Biosci, 13, 3786–3792.

36.

, Li

, Xie

, Zhang

, Guo

, Tang

, et al. (2013). Jagged-1/Notch3 signaling transduction pathway is involved in apelin-13-induced vascular smooth muscle cells proliferation. Acta Biochim Biophys Sin (Shanghai), 45, 875–881.

37.

, Zeng

, and Chen

J.X.

(2012). Apelin-13 increases myocardial progenitor cells and improves repair postmyocardial infarction. Am J Physiol Heart Circ Physiol, 303, H605–H618.

38.

Liu

, Su

, Li

, Qin

, Pan

, et al. (2010). PI3K/Akt signaling transduction pathway is involved in rat vascular smooth muscle cell proliferation induced by apelin-13. Acta Biochim Biophys Sin (Shanghai), 42, 396–402.

39.

Liu

X.H.

, Zhang

Z.Y.

, Sun

, and Wu

X.D.

(2008). Ischemic postconditioning protects myocardium from ischemia/reperfusion injury through attenuating endoplasmic reticulum stress. Shock, 30, 422–427.

40.

, Sun

, and Zheng

(2011). Orientin-induced cardioprotection against reperfusion is associated with attenuation of mitochondrial permeability transition. Planta Med, 77, 984–991.

41.

, Li

, and Chen

(2013). Apelin and APJ, a novel critical factor and therapeutic target for atherosclerosis. Acta Biochim Biophys Sin (Shanghai), 45, 527–533.

42.

, Li

, Lu

, Li

, Xie

, Li

, et al. (2016). PAK1-cofilin phosphorylation mediates human lung adenocarcinoma cells migration induced by apelin-13. Clin Exp Pharmacol Physiol, 43, 569–579.

43.

Manning

A.S.

, and Hearse

D.J.

(1984). Reperfusion-induced arrhythmias: mechanisms and prevention. J Mol Cell Cardiol, 16, 497–518.

44.

Matsui

, Takagi

, Qu

, Abdellatif

, Sakoda

, Asano

, et al. (2007). Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res, 100, 914–922.

45.

Mottaghi

, Larijani

, and Sharifi

A.M.

(2012). Apelin 13: a novel approach to enhance efficacy of hypoxic preconditioned mesenchymal stem cells for cell therapy of diabetes. Med Hypotheses, 79, 717–718.

46.

Mukherjee

, Mareninova

O.A.

, Odinokova

I.V.

, Huang

, Murphy

, Chvanov

, et al. (2016). Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP. Gut, 65, 1333–1346.

47.

O'Dowd

B.F.

, Heiber

, Chan

, Heng

H.H.

, Tsui

L.C.

, Kennedy

J.L.

, et al. (1993). A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene, 136, 355–360.

48.

Pisarenko

, Shulzhenko

, Studneva

, Pelogeykina

, Timoshin

, Anesia

, et al. (2015c). Structural apelin analogues: mitochondrial ROS inhibition and cardiometabolic protection in myocardial ischaemia reperfusion injury. Br J Pharmacol, 172, 2933–2945.

49.

Pisarenko

O.I.

, Lankin

V.Z.

, Konovalova

G.G.

, Serebryakova

L.I.

, Shulzhenko

V.S.

, Timoshin

A.A.

, et al. (2014). Apelin-12 and its structural analog enhance antioxidant defense in experimental myocardial ischemia and reperfusion. Mol Cell Biochem, 391, 241–250.

50.

Pisarenko

O.I.

, Pelogeikina Iu

, Shul'zhenko

V.S.

, Studneva

I.M.

, Bespalova Zh

, Az'muko

A.A.

, et al. (2012b). [The influence of inhibiting no formation on metabolic recovery of ischemic rat heart by apelin-12]. Biomed khim, 58, 702–711.

51.

Pisarenko

O.I.

, Pelogeykina

Y.A.

, Bespalova Zh

, Serebryakova

L.I.

, Sidorova

M.V.

, Az'muko

A.A.

, et al. (2012c). Limitation of myocardial infarction by a structural analog of the peptide apelin-12. Dokl Biol Sci, 443, 65–67.

52.

Pisarenko

O.I.

, Serebryakova

L.I.

, Pelogeykina

Y.A.

, Studneva

I.M.

, Khatri

D.N.

, Tskitishvili

O.V.

, et al. (2011). In vivo reduction of reperfusion injury to the heart with apelin-12 peptide in rats. Bull Exp Biol Med, 152, 79–82.

53.

Pisarenko

O.I.

, Serebriakova

L.I.

, Pelogeikina Iu

, Studneva

I.M.

, Kkhatri

D.N.

, Tskitishvili

O.V.

, et al. (2012a). [Involvement of NO-dependent mechanisms of apelin action in myocardial protection against ischemia/reperfusion damage]. Kardiologiia, 52, 52–58.

54.

Pisarenko

O.I.

, Serebryakova

L.I.

, Studneva

I.M.

, Pelogeykina

Y.A.

, Tskitishvili

O.V.

, Bespalova

Z.D.

, et al. (2013). Effects of structural analogues of apelin-12 in acute myocardial infarction in rats. J Pharmacol Pharmacother, 4, 198–203.

55.

Pisarenko

O.I.

, Shulzhenko

V.S.

, Pelogeikina Iu

, Studneva

I.M.

, Kkhatri

D.N.

, Bespalova Zh

, et al. (2010). [Effects of exogenous apelin-12 on functional and metabolic recovery of isolated rat heart after ischemia]. Kardiologiia, 50, 44–49.

56.

Pisarenko

O.I.

, Shulzhenko

V.S.

, Pelogeykina

Y.A.

, and Studneva

I.M.

(2015a). Enhancement of crystalloid cardioplegic protection by structural analogs of apelin-12. J Surg Res, 194, 18–24.

57.

Pisarenko

O.I.

, Shulzhenko

V.S.

, Studneva

I.M.

, Serebryakova

L.I.

, Pelogeykina

Y.A.

, and Veselova

O.M.

(2015b). Signaling pathways of a structural analogue of apelin-12 involved in myocardial protection against ischemia/reperfusion injury. Peptides, 73, 67–76.

58.

Portman

M.A.

, Zhang

(2005). Myocardial energy transport and heart failure. Curr Cardiol Rev, 1, 17–27.

59.

Rastaldo

, Cappello

, Folino

, Berta

G.N.

, Sprio

A.E.

, Losano

, et al. (2011). Apelin-13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia. Am J Physiol Heart Circ Physiol, 300, H2308–H2315.

60.

Rodriguez-Enriquez

, He

, and Lemasters

J.J.

(2004). Role of mitochondrial permeability transition pores in mitochondrial autophagy. Int J Biochem Cell Biol, 36, 2463–2472.

61.

Ruiz-Meana

, Abellan

, Miro-Casas

, and Garcia-Dorado

(2007). Opening of mitochondrial permeability transition pore induces hypercontracture in Ca2+ overloaded cardiac myocytes. Basic Res Cardiol, 102, 542–552.

62.

Sasaki

, Fukuda

, Otani

, Zhu

, Yamaura

, Engelman

R.M.

, et al. (2002). Hypoxic preconditioning triggers myocardial angiogenesis: a novel approach to enhance contractile functional reserve in rat with myocardial infarction. J Mol Cell Cardiol, 34, 335–348.

63.

Schriewer

J.M.

, Peek

C.B.

, Bass

, and Schumacker

P.T.

(2013). ROS-mediated PARP activity undermines mitochondrial function after permeability transition pore opening during myocardial ischemia-reperfusion. J Am Heart Assoc, 2, e000159.

64.

Schulz

, Kelm

, and Heusch

(2004). Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovasc Res, 61, 402–413.

65.

Shanmuganathan

, Hausenloy

D.J.

, Duchen

M.R.

, and Yellon

D.M.

(2005). Mitochondrial permeability transition pore as a target for cardioprotection in the human heart. Am J Physiol Heart Circ Physiol, 289, H237–H242.

66.

Rahman

, Bopassa

J.C.

, Li

, Umar

, Ciobotaru

(2010). Intralipid induces cardioprotection against ischemia-reperfusion injury by inhibiting the mitochondrial permeability transition pore opening via the PI3K/AKT pathway. Biophys J, 98, 716a–717a.

67.

Simpkin

J.C.

, Yellon

D.M.

, Davidson

S.M.

, Lim

S.Y.

, Wynne

A.M.

, and Smith

C.C.

(2007). Apelin-13 and apelin-36 exhibit direct cardioprotective activity against ischemia-reperfusion injury. Basic Res Cardiol, 102, 518–528.

68.

Soskic

, Klemm

, Proikas-Cezanne

, Schwall

G.P.

, Poznanovic

, Stegmann

, et al. (2008). A connection between the mitochondrial permeability transition pore, autophagy, and cerebral amyloidogenesis. J Proteome Res, 7, 2262–2269.

69.

Szokodi

, Tavi

, Foldes

, Voutilainen-Myllyla

, Ilves

, Tokola

, et al. (2002). Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res, 91, 434–440.

70.

Tao

, Zhu

, Li

, Xin

, Li

, Liu

, et al. (2011). Apelin-13 protects the heart against ischemia-reperfusion injury through inhibition of ER-dependent apoptotic pathways in a time-dependent fashion. Am J Physiol Heart Circ Physiol, 301, H1471–H1486.

71.

Tatemoto

, Hosoya

, Habata

, Fujii

, Kakegawa

, Zou

M.X.

, et al. (1998). Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun, 251, 471–476.

72.

Wang

, Liu

, Luan

, Li

, Wang

, Zou

, et al. (2013b). Apelin protects sarcoplasmic reticulum function and cardiac performance in ischaemia-reperfusion by attenuating oxidation of sarcoplasmic reticulum Ca2+-ATPase and ryanodine receptor. Cardiovasc Res, 100, 114–124.

73.

Wang

, McKinnie

S.M.

, Patel

V.B.

, Haddad

, Wang

, Zhabyeyev

, et al. (2013a). Loss of Apelin exacerbates myocardial infarction adverse remodeling and ischemia-reperfusion injury: therapeutic potential of synthetic Apelin analogues. J Am Heart Assoc, 2, e000249.

74.

Xie

, Liu

, Feng

, Li

, Yang

, Lv

, et al. (2014). A static pressure sensitive receptor APJ promote H9c2 cardiomyocyte hypertrophy via PI3K-autophagy pathway. Acta Biochim Biophys Sin (Shanghai), 46, 699–708.

75.

Yang

, Su

, Lv

, Xie

, Liu

, Cao

, et al. (2014). ERK1/2 mediates lung adenocarcinoma cell proliferation and autophagy induced by apelin-13. Acta Biochim Biophys Sin (Shanghai), 46, 100–111.

76.

Yang

, Li

, Tang

, Ge

, Ma

, Qiao

, et al. (2015). Apelin-13 protects the heart against ischemia-reperfusion injury through the RISK-GSK-3beta-mPTP pathway. Arch Med Sci, 11, 1065–1073.

77.

, Zhang

, Yu

, Luo

, Hua

, Yuan

, et al. (2015). Protective effect of sevoflurane postconditioning against cardiac ischemia/reperfusion injury via ameliorating mitochondrial impairment, oxidative stress and rescuing autophagic clearance. PLoS One, 10, e0134666.

78.

Zeng

X.J.

, Zhang

L.K.

, Wang

H.X.

, Lu

L.Q.

, Ma

L.Q.

, and Tang

C.S.

(2009). Apelin protects heart against ischemia/reperfusion injury in rat. Peptides, 30, 1144–1152.

Apelin/APJ System: A Novel Therapeutic Target for Myocardial Ischemia/Reperfusion Injury

Abstract

Introduction

Protection Roles of the Apelin/APJ System on Myocardial Ischemia–Reperfusion Injury

Protection Mechanisms of the Apelin/APJ System on Myocardial Ischemia–Reperfusion Injury

Apelin/APJ system potentially decreases mitophagy

Apelin/APJ system increases NO formation and promotes recovery of energy metabolism

Apelin/APJ system promotes angiogenesis and recovery of coronary flow

Apelin/APJ system attenuates ER stress

Apelin/APJ system enhances cell membrane integrity

Apelin/APJ system maintains Ca2+ transient

Therapeutic Potential of the Apelin/APJ System in Myocardial Ischemia–Reperfusion Injury

Conclusions

Footnotes

Acknowledgment

Author Disclosure Statement

References

Apelin/APJ system maintains Ca²⁺ transient