Cardiomyocyte PRL2 Promotes Cardiac Hypertrophy via Directly Dephosphorylating AMPKα2.

Abstract

Background: Pathological cardiac hypertrophy can result in heart failure. Protein dephosphorylation plays a primary role in the mediation of various cellular processes in cardiomyocytes. Here, we investigated the effects of a protein tyrosine phosphatase, PRL2 (phosphatase of regenerative liver 2), on pathological cardiac hypertrophy.

Methods: The PRL2 knockout mice were subjected to angiotensin II infusion or transverse aortic constriction to induce myocardial hypertrophy and cardiac dysfunction. RNA-sequencing analysis was performed to explore the underlying mechanisms. Mass spectrometry and bio-layer interferometry assays were used to identify AMPKα2 (AMP-activated protein kinase α2) as an interacting protein of PRL2. Mutant plasmids of AMPKα2 were used to clarify how PRL2 interacts and dephosphorylates AMPKα2.

Results: A significant upregulation of PRL2 was observed in hypertrophic myocardium tissues in mice and patients with heart failure. PRL2 deficiency alleviated cardiac hypertrophy, fibrosis, and dysfunction in mice challenged with angiotensin II infusion or transverse aortic constriction. Transcriptomic and biochemical analyses showed that PRL2 knockout or silence maintained AMPK^T172 phosphorylation and subsequent mitochondrial integrity in angiotensin II-challenged heart tissues or cardiomyocytes. Mass spectrometry-based interactome assay indicated AMPKα2 subunit as the substrate of PRL2. Mechanistically, PRL2 binds to the C-terminal domain of AMPKα2 and then dephosphorylates AMPKα2^T172 via its active site C46. Adeno-associated virus 9-mediated deficiency of cardiomyocyte PRL2 also protected cardiac mitochondrial function and showed cardioprotective effects in angiotensin II-challenged mice, but these benefits were not observed in AMPKα2^-/- mice.

Conclusions: This study reveals that PRL2, as a novel AMPK-regulating phosphatase, promotes mitochondrial instability and hypertrophic injury in cardiomyocytes and provides PLR2 as a potential target for future drug development treating heart failure.