Role of protein phosphatase 2A in cardiac function.

摘要

The purpose of this study was to identify acute and chronic functional roles of protein phosphatase 2A (PP2A), and potential PP2A regulatory mechanisms in the heart. It was found that PP2A is physiologically regulated through adenosine A₁ receptor activation which, in turn, modulates the phosphorylation state of the cardiac regulatory proteins phospholamban and troponin I. Moreover, activation of cardiac PP2A by adenosine A₁ receptors involves carboxymethylation on the PP2A catalytic subunit and translocation of the PP2A holoenzyme. Additional studies demonstrated that PP2A translocation/activation by adenosine A₁ receptors requires activation of a Gi-cGMP-p38 MAPK pathway in cardiac myocytes. This pathway contributes to acute anti-adrenergic effects in the heart. Chronic studies focused on understanding the role of PP2A in the regulation of MAP kinase signaling and apoptosis in cardiac myocytes. PP2A activation was found to be required for the negative cross-talk between p38 MAPK and ERK pathways in cardiomyocytes. Further, PP2A co-immunoprecipitates with ERK and MEK in cardiac myocytes, and H₂O ₂ increased the PP2A-ERK association through a p38-dependent mechanism. H₂O-induced cardiomyocyte apoptosis was attenuated by p38 MAPK or PP2A inhibition, whereas it was enhanced by MEK inhibition. This PP2A-mediated cross-talk between p38 MAPK and ERK represents a novel mechanism that allows for the fine modulation of the chronic cellular response such as apoptosis following oxidative stress.