Cardiovascular Effects of Apelins: Comparison
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In-hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) is 5–6%. Consequently, it is necessary to develop fundamentally novel drugs capable of reducing mortality in patients with acute myocardial infarction. Apelins could be the prototype for such drugs. Chronic administration of apelins mitigates adverse myocardial remodeling in animals with myocardial infarction or pressure overload. The cardioprotective effect of apelins is accompanied by blockage of the MPT pore, GSK-3β, and the activation of PI3-kinase, Akt, ERK1/2, NO-synthase, superoxide dismutase, glutathione peroxidase, matrix metalloproteinase, the epidermal growth factor receptor, Src kinase, the mitoKATP channel, guanylyl cyclase, phospholipase C, protein kinase C, the Na+/H+ exchanger, and the Na+/Ca2+ exchanger. The cardioprotective effect of apelins is associated with the inhibition of apoptosis and ferroptosis.

  • heart
  • ischemia/reperfusion
  • apelin

1. The Expression of Apelins and Their Receptor in Rats and Humans

Apelin-12 was detected in human left ventricular tissue [23][1]. Apelin-12 is localized in the endothelial and smooth muscle cells of coronary arteries and also in cardiomyocytes [23][1]. The immunohistochemical method was used for detection of apelin and the apelin receptor in the rat heart [24][2]. Western blot was also used to measure the apelin levels. High apelin levels were found especially in endothelial cells and perivascular mast cells. Apelin was not detected in cardiomyocytes or fibroblasts. The apelin receptor was found in endothelial cells, cardiomyocytes, and vascular smooth muscle cells but not in fibroblasts and mast cells [24][2]. The endogenous agonist of the apelin receptor apela mRNA was detected in the rat heart [18][3]. It was demonstrated that the apelin receptor is expressed in the atrial tissue and heart ventricles of rats [25][4] and in the human heart [26][5]. The apelin receptor was identified in the epicardial coronary arteries of rats [27][6].
Apelin is synthesized by cardiac endothelial and mast cells. The apelin receptor is expressed by endothelial cells, smooth muscle cells, and cardiomyocytes.

2. The Effects of Apelins on Blood Pressure and Heart Rate

It was reported that apelin-13 can decrease blood pressure (BP) and increase heart rate (HR) [28,29,30,31,32,33][7][8][9][10][11][12].
Apelin-13 was injected intravenously at a dose of 6 µg/kg in anesthetized rats. This peptide triggered a transient reduction in BP without significant alteration of HR [28][7]. Pyr1-apelin-13 (10 nmol/kg = 15 µg/kg) increased HR in anesthetized rats by 11 beats/min and had no effect on HR in rats in an awake state [29][8]. Pyr1-apelin-13 at a dose of 65 nmol/kg (98 µg/kg) increased HR by 14 beats/min in rats in an awake state. Pyr1-apelin-13 at a dose of 10 nmol/kg had no effect on BP and reduced BP at a dose of 60 nmol/kg in anesthetized rats. Both effects were transient [29][8]. Apelin-12 at a dose of 0.07 µmol/kg (0.1 mg/kg) intravenously decreased BP by 20% at a dose of 0.35 µmol/kg (0.5 mg/kg) reduced BP by 40% [34][13]. This effect was transient. Intravenous infusion of Pyr1-apelin-13 induced forearm vasodilation in patients with heart failure and control subjects [35][14]. Acetylcholine- but not apelin-13-induced vasodilation was reduced in patients with heart failure. Intracoronary injection of apelin-36 increased the maximum rate of rise in left ventricular pressure and coronary blood flow [35][14]. Intravenous infusion of Pyr1-apelin-13 increased the cardiac index, lowered BP, and reduced peripheral vascular resistance in control subjects and patients with heart failure. Apelin increased HR only in healthy subjects [35][14].
The hypotensive effect of apelins is apparently the result of their direct effect on arteries. Pyr1-apelin-13, apelin-13, and apelin-36 induced a concentration-dependent vasodilatation of isolated endothelium-intact human mammary arteries preconstricted with endothelin-1 [36][15]. EC50 was 0.6 to 1.6 nM. Arterial rings (120–150 µm; 1.2 mm in length) were prepared from coronary arteries of rats [27][6]. Rings were precontracted with 5-hydroxytryptamine. Apelin-13 induced vasodilation of the coronary arteries at the final concentration of 10 nmol/L. The apelin receptor antagonist F13A and the NOS inhibitor nitro-L-arginine (NLA) abolished apelin-induced vasodilation.
Thus, NOS plays a key role in apelin-induced vasodilation.

3. The Effect of Apelins on the Contractile Function of the Heart

In a study with an isolated rat heart, infusion of apelin-16 at a final concentration of 0.01 to 10 nmol/L induced a dose-dependent positive inotropic effect (EC50: 33 pmol/L) [37][16]. The positive inotropic effect of apelin-16 peaked at 1 nmol/L. U-73122, a phospholipase C (PLC) inhibitor, completely abolished any positive inotropic effect of apelin-16. Staurosporine and GF-109203X, protein kinase C (PKC) inhibitors, mitigated but did not eliminate the apelin-16-induced inotropic effect. The Na+-H+ exchange (NHE) isoform-1 inhibitor zoniporide and Na+-Ca2+ exchange (NCX) inhibitor KB-R7943 mitigated but did not abolish an inotropic effect of apelin-16. Apelin-16 had no effect on L-type Ca2+ current or voltage-activated K+ currents in isolated adult rat ventricular myocytes [37][16]. Consequently, a key role in the inotropic effect of apelin-16 belongs to PLC. PKC, NHE, and NCX also are involved in the positive inotropic effect of apelin. In a study with isolated electrically stimulated rat cardiomyocytes, it was found that apelin-16 (1 nmol/L) increases [Ca2+]i transients and fractional shortening (FS) [38][17]. Apelin-16 increased the total cytosolic Ca2+ concentration and reduced sarcoplasmic reticulum (SR) Ca2+ content. Apelin-16 increased SR Ca2+-ATPase (SERCA) activity, and this effect was completely abolished by chelerythrine. It was concluded that PKC and SERCA are involved in the positive inotropic effect of apelin-16 [38][17].
Intravenous administration of apelin-13 (40 and 60 μg/kg) induced transient (5–6 min) positive inotropic and hypotensive effects in renovascular hypertensive (2K1C) rats [39][18]. Pretreatment with the κ-opioid receptor (κ-OR) antagonist nor-binaltorphimine, the Gi/o proteins’ inhibitor pertussis toxin, and chelerythrine abolished a positive inotropic effect of apelin-13 (60 μg/kg). Investigators concluded that there is heterodimerization between the κ-OR and apelin receptor [39][18]. It was found that intravenous injection of Pyr1-apelin-13 (10 µg/kg, intravenously) increased cardiac output and stroke volume in anesthetized rats by 15% and 12%, respectively [22][19]. An increase in dose up to 100 µg/kg did not increase the positive inotropic effect of Pyr1-apelin-13.
These data indicated that apelins exhibit a positive inotropic effect both in vivo and in vitro at the level of the isolated heart or isolated cardiomyocytes. This effect is mediated via PLC, PKC, Gi/o proteins, κ-OR, ERK1/2, and SERCA. The role of NHE and NCX in the inotropic effect of apelin is minimal. Investigators did not use the apelin receptor antagonist; therefore, it is unclear whether this effect is mediated via activation of the apelin receptor in cardiomyocytes.

4. The Cardioprotective Effect of Apelins in Ischemia and Reperfusion of the Heart

The isolated mouse heart was subjected to global ischemia (30 min) and reperfusion (35 min) [40][20]. The heart was perfused with a solution containing apelin-13 (1 µmol) during reperfusion (35 min). Apelin-13 reduced infarct size by about 40%. Mice underwent coronary artery occlusion (CAO, 30 min) and reperfusion (120 min). Injection of apelin-13 (1 mg/kg) in reperfusion contributed to infarct size reduction by about 40%. An increase in a dose of apelin did not increase the infarct-reducing effect of apelin-13. Apelin-36 exhibited a weaker infarct-sparing effect than apelin-13 [40][20]. Thus, apelins limited infarct size in reperfusion through a direct effect on the heart. The isolated perfused rat heart was subjected to CAO (35 min) and reperfusion (30 min) [41][21]. The heart was perfused a solution with Pyr1-apelin-13 (10 nmol/L) prior to ischemia or after ischemia. Apelin reduced infarct size in reperfusion by about 15% and had no effect if it was used prior to ischemia. Apelin did not improve the contractile function of the heart in reperfusion [41][21]. The isolated rat heart was subjected to global ischemia (40 min)/reperfusion (30 min) [42][22]. The heart was perfused with Krebs–Henseleit buffer containing apelin-13 (30 pmol/L). Apelin-13 improved the recovery of the contractile function of the heart, reduced lactate dehydrogenase (LDH) release in the coronary effluent, and decreased malondialdehyde (MDA) content in myocardial tissue. Surprisingly, apelin-13 at such a low concentration (30 pmol/L) showed a cardioprotective effect. This concentration was lower than the Ki (64 pmol/L) for apelin [22][19]. Apparently, this result is a statistical error associated with the use of the small group of animals (n = 6).
The isolated perfused rat heart was then subjected to global ischemia (35 min) and reperfusion (30 min) [43][23]. The heart was perfused with a solution containing apelin-12 (35, 70, 140, 280, and 560 μmol/L) prior to ischemia or at the onset of reperfusion. Apelin-12 improved the recovery of contractile function after ischemia. The effect reached its maximum at a final concentration of apelin-12 of 140 μmol/L (n = 8) [43][23]. Apelin-12 had a more pronounced inotropic effect if it was infused prior to ischemia. Infusion of apelin-12 (140 μmol/L) prior to ischemia promoted an increase in ATP levels by 58%, induced a reduction in lactate content in myocardial tissue by 20%, and reduced LDH release in reperfusion [43][23]. Investigators hypothesized that the cardioprotective effect of apelin-12 could be due to improved energy metabolism. Rats were subjected to CAO (40 min) and reperfusion (60 min) [34][13]. Intravenous administration of apelin-12 at a dose of 0.07 µmol/kg (0.1 mg/kg) reduced infarct size by 21%, at a dose of 0.35 µmol/kg (0.5 mg/kg) by 34% in reperfusion [34][13]. It was found that apelin-12 at a dose of 0.35 µmol/kg (0.5 mg/kg, intravenously) reduced infarct size by 40% in rats with reperfusion of the heart after CAO (40 min) [44][24]. Apelin-12 reduced infarct size by 33% at a dose of 0.7 µmol/kg (1 mg/kg). The isolated rat heart was subjected to global ischemia (30 min) and reperfusion (120 min) [45][25]. The heart was perfused with a solution containing apelin-13 (0.5 µmol/L) prior to ischemia (20 min) or in reperfusion (20 min). Pretreatment with apelin-13 before ischemia did not reduce infarct size. Infusion of apelin-13 reduced infarct size by about 60% in reperfusion [45][25]. Apelin-13 (0.1. 1, and 10 µg/kg) was injected intravenously after CAO (30 min) 15 min prior to reperfusion (2 h) in rats [46][26]. Apelin-13 at a dose of 0.1 µg/kg reduced infarct size by about 30%; this peptide at a dose of 1 µg/kg decreased infarct size by approximately 40%; and at a dose of 10 µg/kg, it reduced infarct size by about 30% [46][26]. Apelin-13 (1 µg/kg) reduced a number of TUNEL-positive (apoptotic) cells in myocardial tissue, decreased caspase-3 activity, and reduced the levels of phosphorylated c-Jun N-terminal kinases (p-JNK) and cleaved-caspase-12 [46][26]. Consequently, apelin-13 prevents necrosis and apoptosis in the reperfusion of the heart. The use of too high of a dose of apelin-13 may lead to the disappearance of the infarct-reducing effect.
A comparative analysis of the cardioprotective properties of apelin-12 and its analogue Nα-MeArg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-ProPhe-OH (AI) was performed in a study with a rat heart subjected to ischemia/reperfusion (I/R) both in vivo and in vitro in reperfusion [47][27]. It was found that both peptides (0.35 µmol/kg) exhibited an identical infarct-reducing effect in vivo. Both peptides improved the recovery of contractile function of the heart in reperfusion in vitro [47][27]. Myocardial infarct could affect apelin and apelin receptor expression in the heart. Permanent CAO induced a reduction in the apelin and apelin receptor levels in myocardial tissue 7 days after coronary artery occlusion in mice [48][28]. Apelin knockout promoted an increase in infarct size by about 36%, reduced survival of mice with permanent CAO, and aggravated apoptosis in the heart after CAO. A disturbance of apelin expression contributed to a decrease in the p-Akt and p-ERK1/2 levels in myocardial tissue after myocardial infarction (MI). Apelin knockout enhanced neutrophil and macrophage invasion in the mouse heart after CAO, increased TNF-α, IL-1β, and IL-6 content in myocardial tissue and aggravated contractile dysfunction after MI [47][27]. A disturbance of apelin expression disrupts the recovery of contractile function of the isolated mouse heart after ischemia (30 min) and reperfusion (40 min). Pyr1-apelin-13 analogue II improved the recovery of contractile function of the isolated heart. Apelin knockout reduced hypoxia-inducible factor-1α (HIF-1α) and VEGF and suppressed myocardial angiogenesis after MI [48][28]. Consequently, apelins increase cardiac tolerance to I/R and participate in myocardial angiogenesis after MI.
Isolated rat hearts were subjected to global ischemia (30 min) and reperfusion (30 min) [49][29]. Hearts were perfused with a solution containing apelin-13 (1 nmol/L–1 µmol/L) before and after ischemia. Apelin (0.1–1 µmol/L) reduced LDH release, improved recovery of the contractile function of the heart in reperfusion, decreased MDA, nitrotyrosine, and lactate content in myocardial tissue, and increased the reduced glutathione level in the heart. Apelin restored sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity and 3H-ryanodine binding [49][29]. Consequently, the improvement in the contractile function of the heart could be a result of increased SERCA activity and ryanodine receptor density in cardiomyocytes.

5. Apelins Prevent Adverse Myocardial Remodeling

Apelin-13 (1 mg/kg/day) was injected intraperitoneally for 3 days before permanent CAO and for 14 days after CAO [55][30]. Apelin-13 reduced infarct size and decreased a number of TUNEL-positive cells 24 h after CAO by about 40%. Apelin-13 promoted an increase in the p-Akt, p-eNOS, and VEGF levels in myocardial tissue 24 h after CAO. Apelin triggered the homing of CD133+/c-Kit+/Sca1+ vascular progenitor cells in the infarcted heart. Apelin-13 increased myocardial capillary and arteriole density 14 days after MI. Chronic administration of apelin-13 prevented cardiac hypertrophy and improved cardiac contractile function 14 days after CAO [55][30]. Apelin-13 (1–100 nM) inhibited collagen synthesis by mouse cardiac fibroblasts [56][31]. The molecular mechanism of this effect is unclear because cardiac fibroblasts do not express the apelin receptor [24][2]. Apelin-13 stimulated the proliferation of H9c2 cardiomyoblasts [57][32]. The maximum effect was observed at a concentration of 200 nmol/L. The effect disappeared at a concentration of 800 nmol/L [57][32]. These data are credible because the apelin receptors are expressed on cardiomyocytes [24][2].
Apelin-13 was injected intraperitoneally at a dose of 20 nmol/kg/day to rats with permanent CAO for 28 days [58][33]. Chronic administration of apelin-13 improved the contractile function of the heart 28 days after MI and reduced infarct size. Investigators wrote that they used Pfeffer’s method for the evaluation of infarct size. However, Pfeifer et al. wrote that they measured fibrous infarct 14 days after CAO [59][34]. Therefore, it should be more correctly written that apelin decreased scar size. Apelin-13 at a final concentration of 1 µmol/L increased the proliferation of cardiac microvascular endothelial cells.
Rats underwent CAO (30 min) and reperfusion (14 days) [60][35]. Pyr1-Apelin-13 was injected intraperitoneally at a dose of 10 nmol/kg/day (15 µg/kg/day) for 5 days beginning 24 h after CAO. Pyr1-apelin-13 improved the contractile function of the heart and reduced the fibrosis area by about 60%. Apelin increases the VEGF mRNA, VEGF receptor-2 (Kdr) mRNA, and angiopoietin-1 (Ang-1) mRNA, eNOS, and mRNA levels in myocardial tissue. In addition, chronic administration of Pyr1-Apelin-13 prevents apoptosis of cardiomyocytes [61][36]. Investigators concluded that Pyr1-apelin-13 exhibits angiogenic and anti-fibrotic effects via the formation of new blood vessels and enhancement of the expression of VEGFA, Kdr, Ang-1, and eNOS in the infarcted myocardium [60][35].
Rats underwent permanent CAO [62][37]. Adverse cardiac remodeling was developed 28 days after CAO. Apelin-13 (10 nmol/kg/day, intraperitoneally) was administered for 28 days. Myocardial infarction resulted in an increase in apelin and apelin receptor expression by about 2-fold. Chronic administration of apelin-13 prevented the development of contractile dysfunction and cardiac fibrosis. In a study with isolated cardiac fibroblasts, apelin-13 suppressed angiotensin II-induced collagen synthesis by these cells. Apelin-13 reduced the PI3-kinase and p-Akt levels in cardiac fibroblasts stimulated by angiotensin II. Myocardial infarction (28 days) simulated NADPH oxidase activity and increased superoxide production in the heart. Chronic administration of apelin-13 reversed these alterations. Investigators concluded that apelin-13 prevents adverse post-infarction remodeling of the heart through the inhibition of oxidative stress and suppression of the PI3-kinase/Akt pathway in cardiac fibroblasts [62][37].
The endogenous apelin receptor agonist apela (1 mg/kg/day) was continuously administered to mice with permanent CAO for 2 weeks by an osmotic minipump [63][38]. Apela reduced serum N-terminal brain natriuretic peptide (NT-proBNP) concentration and increased the left ventricular ejection fraction (LVEF) 2 and 4 weeks after MI. Apela reduced infarct size and interstitial fibrosis 4 weeks after MI. The accuracy of infarct size measurement 4 weeks after permanent CAO is questionable because 4 weeks after MI, a scar is formed in the infarcted myocardium [64][39]. Apela increased the expression of neovascular endothelial cell marker CD31 by about 20%. Apela reduced a number of TUNEL-positive and myeloperoxidase-positive cells [63][38].

6. The Effects of Apelins on Regulated Cell Death

There are five main regulated forms of cell death: apoptosis, autophagy, pyroptosis, necroptosis, and ferroptosis. It has been found that apelins exhibit anti-apoptotic properties in I/R of the heart [42,46,52,61,67,68][22][26][36][40][41][42]. Apelin-13 (30 pmol/L) abolished the hypoxia/reoxygenation-induced apoptosis of isolated neonatal cardiomyocytes [42][22]. Rats underwent CAO (30 min) and reperfusion (4 h) [68][42]. Elabela (700 µg/kg) was injected intravenously 5 min before reperfusion. Elabela reduced collagen expression and decreased a number of TUNEL-positive cells in myocardial tissue. Elabela increased the ATP and glutathione (GSH) levels in the heart and reduced ROS production and MDA content in myocardial tissue [68][42].
These data indicate that apelins have an anti-apoptotic effect in I/R of the heart. This effect could be involved in the cardioprotective effects of apelins.
Specific markers of ferroptosis do not exist [69][43]. This form of cell death is accompanied by a rupture of the cell membrane. An increase in MDA and 4-hydroxynonenal levels is an indicator of ferroptosis [69][43]. It was demonstrated that apelins reduced MDA levels in myocardial tissue and suppressed oxidative stress in I/R [42,49,68][22][29][42]. The cardioprotective effect of elabela is associated with the inhibition of ferroptosis in mice with pressure overload remodeling of the heart [66][44]. Consequently, apelins could inhibit ferroptosis in the heart.
However, convincing evidence is required to show that this inhibition is directly related to the cardioprotective effects of apelins.
Autophagy is a form of cell death without a rupture of the cell membrane [70][45]. There is evidence that the activation of autophagy increased cardiac tolerance to I/R [71,72,73][46][47][48]. Apelin-13 triggered hypertrophy in H9c2 [74][49]. This effect was associated with the activation of autophagy. Intramyocardial injection of adenovirus-apelin stimulated autophagy in mice with streptozotocin-induced diabetes [75][50]. Apelin-13 activated the autophagy of HL-1 cells pretreated with angiotensin II through the activation of AMPK and inhibition of mTOR [76][51].
Thus, there is evidence that the cardioprotective effects of apelins are associated with the inhibition of apoptosis, ferroptosis, and stimulation of autophagy. The roles of necroptosis and pyroptosis in the apelin-induced tolerance of the heart remain unclear.

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