XIAP expression attenuated myocardial injury in aging hearts after myocardial ischemia and reperfusion in mice model

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Seiho Matsuda, Juan Nakamura, Stephen Eikan, Robert Meier, Khanh Katz, Jue Richter, Detlef Mazzon^*

∗Correspondence author e-mail: Detlef_Mazzon@yahoo.com: ¹Massachusetts Department of Public Health, Jamaica Plain, Massachusetts, USA

Abstract

Myocardial ischemia and reperfusion (I/R) injury is crucial in heart disease pathology. Aging increases vulnerability to I/R, emphasizing the need for targeted therapeutics. XIAP, an innate pathway inhibitor, protects against cell death by inhibiting caspases and effector proteins. Herein, we investigate how XIAP prevents myocardial I/R injury in aging hearts using genetic models and signaling pathway analysis to shed light on the impact of XIAP on aging heart susceptibility to I/R injury. Ischemic heart disease, primarily sustained occlusion of coronary arteries, prevents oxygen and glucose delivery and leads to cell lysis and myocardial necrosis. Restoration of blood flow can also lead to cytotoxic insults, so this phenomenon is called ischemia and reperfusion injury (I/R injury). Mouse models created by temporarily occluding the left anterior descending (LAD) coronary artery followed by reperfusion have been widely used for studying I/R injury. Myocardial I/R injury is aggravated by aging in patients and animal models. The bivalent inhibitor I-VII of the mitochondrial protease OMA1 has been shown to prevent global cell death, neurodegeneration, and accidental death in aging mice. However, heart-specific protection and signaling pathways have not been thoroughly elucidated. X-linked inhibitor of apoptosis protein (XIAP) is a potent innate pathway apoptosis inhibitor. XIAP inhibits procaspase-3 and procaspase-9 through its BIR3 domain and inhibits effector proteins Smac/DIABLO, HtrA2/Omi, and ARTS/DIABLO through a BIR2 domain. XIAP has been shown to protect from H2O2-induced cell death in cardiomyocyte and fibroblast cell lines. XIAP deficiency in adult hearts reduces heart size and promotes apoptosis and hypertrophy. XIAP overexpression in the mouse heart was shown to globally inhibit caspases, abnormal stress signaling pathways, and cell hypertrophy in transgenic mice. In aged hearts following I/R, XIAP overexpression reduces cell death, promotes cell recovery, and preserves heart function, demonstrating the critical role of XIAP expression in attenuating myocardial injury in aging hearts following I/R in a mouse model.

Keywords: XIAP; Aging; Ischemia/Reperfusion; LV function; Apoptosis; Myocardial injury

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