Exogenous Ubiquitin Attenuates Hypoxia/Reoxygenation-Induced Cardiac Myocyte Apoptosis via the Involvement of CXCR4 and Modulation of Mitochondrial Homeostasis
Exogenous ubiquitin (UB) plays a protective role in β-adrenergic receptor-stimulated and ischemia/reperfusion (I/R)-induced myocardial remodeling. Here, we report that UB treatment inhibits hypoxia/reoxygenation (H/R)-induced apoptosis in adult rat ventricular myocytes (ARVMs). The activation of Akt was elevated, whereas the activation of glycogen synthase kinase-3β was reduced in UB-treated cells post-H/R. The level of oxidative stress was lower, whereas the number of ARVMs with polarized mitochondria was significantly greater in the UB-treated samples. ARVMs express CXCR4 with majority of CXCR4 localized in the membrane fraction. CXCR4 antagonism using AMD3100, and siRNA-mediated knockdown of CXCR4 negated the protective effects of UB. Two mutated UB proteins (unable to bind CXCR4) had no effect on H/R-induced apoptosis, activation of Akt and GSK-3β, or oxidative stress. UB treatment enhanced mitochondrial biogenesis, and inhibition of mitochondrial fission using mdivi1 inhibited H/R-induced apoptosis. Ex vivo, UB treatment significantly decreased infarct size and improved functional recovery of the heart following global I/R. Activation of caspase-9, a key player of the mitochondrial death pathway, was significantly lower in UB-treated hearts post-I/R. UB, most likely acting via CXCR4, plays a protective role in H/R-induced myocyte apoptosis and myocardial I/R injury via modulation of mitochondrial homeostasis and the mitochondrial death pathway of apoptosis.
Dalal, Suman; Daniels, Christopher R.; Li, Ying; Wright, Gary L.; Singh, Mahipal; and Singh, Krishna. 2020. Exogenous Ubiquitin Attenuates Hypoxia/Reoxygenation-Induced Cardiac Myocyte Apoptosis via the Involvement of CXCR4 and Modulation of Mitochondrial Homeostasis. Biochemistry and Cell Biology. Vol.98(4). 492-501. https://doi.org/10.1139/bcb-2019-0339 PMID: 31967865 ISSN: 0829-8211