Journal
BIOCHEMISTRY AND CELL BIOLOGY
Volume 98, Issue 4, Pages 492-501Publisher
CANADIAN SCIENCE PUBLISHING
DOI: 10.1139/bcb-2019-0339
Keywords
apoptosis; CXCR4; heart; myocytes; ubiquitin
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Funding
- Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Merit Review Awards [BX000640, BX004045]
- National Institutes of Health (NIH) [R15HL141947]
- NIH [C06RR0306551]
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Exogenous ubiquitin (UB) plays a protective role in beta-adrenergic receptor-stimulated and ischemialreperfusion (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-3 beta was reduced in UB-treated cells post-MR. 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-3 beta, or oxidative stress. UB treatment enhanced mitochondrial biogenesis, and inhibition of mitochondrial fission using mdivi1 inhibited MR-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 mitochondria' death pathway, was significantly lower in UB-treated hearts post-I/R. UB, most likely acting via CXCR4, plays a protective role in MR-induced myocyte apoptosis and myocardial I/R injury via modulation of mitochondria' homeostasis and the mitochondria' death pathway of apoptosis.
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