Abstract
It is known that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission plays an important role in ischemic injury of myocardial infarction (MI). Apelin, an endogenous ligand for Apelin receptor, acts as a key modulator of cardiovascular diseases. Here, we examined the effects of Apelin on MI injury and underlying mechanisms. Adult male C57BL/6J mice were treated with Apelin for 4 weeks and then subjected coronary artery ligation (LAD) to induce MI and the protective effects of Apelin on MI injury were evaluated at 6 h post LAD. Mitochondrial fission was significantly increased in MI as evidenced by enhanced expression of phosphorylated Drp1 (p-Drp1ser 616) without affecting total Drp-1 level and degenerative transformation of mitochondria into short rods as typical fission. Apelin markedly inhibited p-Drp1ser 616 and preserved mitochondrial morphology in MI. Similar effects of Apelin were consistently observed in primary cultured cardiomyocytes under hypoxia. Apelin decreased hypoxia-induced cardiomyocyte apoptosis as evidenced by decreased TUNEL-positive cells and preserved mitochondrial membrane potential (MMP). Apelin decreased Bax/Bcl-2 ratio and limited the release of cytochrome C and activation of caspase-9 and caspase-3 both in vivo and in vitro. Finally, Apelin diminished the infarct size and normalized the impaired cardiac function as indicated by rescuing of the decreased ejection faction and fractional shortening in MI mice. In conclusion, Apelin prevented mitochondrial fission by inhibiting p-Drp1Ser616, which prevents loss of MMP and inhibits the mitochondria-mediated apoptosis. These results indicate that the inhibition of Drp-1 activation by Apelin is a novel mechanism of cardioprotection against MI injury.
Highlights
Myocardial infarction (MI) is still a primary cause of death in the world with an increased risk of morbidity and mortality [1,2,3]
It is known that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission plays an important role in ischemic injury of myocardial infarction (MI)
With Apelin treatment, the number of cardiomyocytes with mitochondrial fission induced by hypoxia was substantially decreased (Figure 1C & 1D)
Summary
Myocardial infarction (MI) is still a primary cause of death in the world with an increased risk of morbidity and mortality [1,2,3]. Many cardioprotective pharmacological agents failed to exert their protective effects [4,5,6]. While many interventions are effective in reducing MI injury and offering limited protection against ischemia/. Increased mitochondrial fission in the ischemic heart contributes to apoptosis induction and infarct generation, while inhibiting mitochondrial fission reduces myocardial injury and improves cardiac function following MI [12, 13]. Ding et al [15] reported that Drp1mediated mitochondrial fission is increased following I/R under diabetic conditions and its inhibition with Mdivi-1 reduces I/R injury and improves cardiac function. Inhibition of Drp has been demonstrated to reduce mitochondrial fission and infarct size during ischemic injury in animals [17, 18]. Manipulating Drp1-dependent mitochondrial fission may be an alternative strategy for the development of new anti-apoptotic drugs
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