Loss of PKA regulatory subunit 1α aggravates cardiomyocyte necrosis and myocardial ischemia/reperfusion injury.

Abstract

Reperfusion therapy, the standard treatment for acute myocardial infarction, can trigger necrotic death of cardiomyocytes and provoke ischemia/reperfusion (I/R) injury. However, signaling pathways that regulate cardiomyocyte necrosis remain largely unknown. Our recent genome-wide RNAi screen has identified a potential necrosis suppressor gene PRKAR1A, which encodes PKA regulatory subunit 1α (R1α). R1α is primarily known for regulating PKA activity by sequestering PKA catalytic subunits in the absence of cAMP. Here, we showed that depletion of R1α augmented cardiomyocyte necrosis in vitro and in vivo, resulting in exaggerated myocardial I/R injury and contractile dysfunction. Mechanistically, R1α loss downregulated the Nrf2 antioxidant transcription factor and aggravated oxidative stress following I/R. Degradation of the endogenous Nrf2 inhibitor Keap1 through p62-dependent selective autophagy was blocked by R1α depletion. Phosphorylation of p62 at Ser349 by mammalian target of rapamycin complex 1 (mTORC1), a critical step in p62-Keap1 interaction, was induced by I/R, but diminished by R1α loss. Activation of PKA by forskolin or isoproterenol almost completely abolished hydrogen-peroxide-induced p62 phosphorylation. In conclusion, R1α loss induces unrestrained PKA activation and impairs the mTORC1-p62-Keap1-Nrf2 antioxidant defense system, leading to aggravated oxidative stress, necrosis, and myocardial I/R injury. Our findings uncover a novel role of PKA in oxidative stress and necrosis, which may be exploited to develop new cardioprotective therapies.

• Authors: Yuening Liu, Jingrui Chen, Peng Xia, Constantine A Stratakis, Zhaokang Cheng
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 297 Issue 1 Pg. 100850 (07 2021) ISSN: 1083-351X [Electronic] United States
• PMID: 34087234 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Catecholamines
• Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
• Keap1 protein, mouse
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• P62 protein, human
• Prkar1a protein, mouse
• RNA-Binding Proteins
• Receptors, Adrenergic
• Adenylyl Cyclases

Topics

• Adenylyl Cyclases (genetics)
• Animals
• Carney Complex (genetics, pathology, therapy)
• Catecholamines (metabolism)
• Cyclic AMP-Dependent Protein Kinase RIalpha Subunit (genetics)
• Disease Models, Animal
• Humans
• Kelch-Like ECH-Associated Protein 1 (genetics)
• Mice
• Mitochondrial Transmembrane Permeability-Driven Necrosis (genetics)
• Myocardial Reperfusion Injury (genetics, pathology, therapy)
• Myocytes, Cardiac (metabolism, pathology)
• NF-E2-Related Factor 2 (genetics)
• Oxidative Stress (genetics)
• Phosphorylation (genetics)
• RNA-Binding Proteins (genetics)
• Rats
• Receptors, Adrenergic (genetics)
• Signal Transduction (drug effects)