1. p85α deficiency alleviates ischemia-reperfusion injury by promoting cardiomyocyte survival.
- Author
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Zhu K, Liu Y, Dai R, Wang X, Li J, Lin Z, Du L, Guo J, Ju Y, Zhu W, Wang L, and Cao CM
- Subjects
- Animals, Mice, Humans, Glycogen Synthase Kinase 3 beta metabolism, Glycogen Synthase Kinase 3 beta genetics, Male, bcl-X Protein metabolism, bcl-X Protein genetics, Cell Survival, Class Ia Phosphatidylinositol 3-Kinase metabolism, Class Ia Phosphatidylinositol 3-Kinase genetics, Apoptosis, Mice, Inbred C57BL, Mice, Knockout, Phosphorylation, Tumor Suppressor Protein p53, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardial Reperfusion Injury genetics, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-akt genetics, Signal Transduction
- Abstract
Myocardial ischemia-reperfusion (I/R) injury is a prevalent cause of myocardial injury, involving a series of interconnected pathophysiological processes. However, there is currently no clinical therapy for effectively mitigating myocardial I/R injury. Here, we show that p85α protein levels increase in response to I/R injury through a comprehensive analysis of cardiac proteomics, and confirm this in the I/R-injured murine heart and failing human myocardium. Genetic inhibition of p85α in mice activates the Akt-GSK3β/Bcl-x(L) signaling pathway and ameliorates I/R-induced cardiac dysfunction, apoptosis, inflammation, and mitochondrial dysfunction. p85α silencing in cardiomyocytes alleviates hypoxia-reoxygenation (H/R) injury through activating the Akt-GSK3β/Bcl-x(L) signaling pathway, while its overexpression exacerbates the damage. Mechanistically, the interaction between MG53 and p85α triggers the ubiquitination and degradation of p85α, consequently enhancing Akt phosphorylation and ultimately having cardioprotective effects. Collectively, our findings reveal that substantial reduction of p85α and subsequently activated Akt signaling have a protective effect against cardiac I/R injury, representing an important therapeutic strategy for mitigating myocardial damage., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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