Myocardial overexpression of protein phosphatase 2A-B56α improves resistance against ischemia-reperfusion injury.

Protein phosphatase 2A (PP2A) plays a central role in myocardial ischemia-reperfusion (I/R) injury. Several studies showed a detrimental function of PP2A by using either overexpression models of the catalytic subunit (PP2Ac) or exogenous inhibitors of PP2Ac. However, all of these approaches underestimate the contribution of regulatory B subunits in modulating the PP2A holoenzyme. To better understand the influence of B subunits on a "controlled" regulation of PP2A, we tested a mouse model overexpressing PP2A-B56α (TG) in the heart under the conditions of I/R in comparison to wild-type littermates (WT). Contractility was increased after reperfusion in isolated TG hearts that were initially subjected to a 20-min no-flow ischemia. This was associated with lower phosphorylation levels of myosin-binding protein C and the ryanodine receptor 2 in TG compared to WT. The application of okadaic acid abolished the contractile and biochemical effects in TG hearts. Moreover, reperfusion resulted in the detection of higher PP2A-B56α levels in mitochondrial preparations of TG hearts. The phosphorylation of ERK1 was increased in the early reperfusion phase in TG compared to WT hearts corresponding to a transient attenuation of PP2A activity. Ischemia led to a prolonged contracture time in TG hearts and a lower acidification in isolated TG cardiomyocytes. The formation of interstitial fibrosis by transient ligation of the left anterior descending (LAD) artery was reduced in TG compared to WT hearts. Taken together, these findings indicate that overexpression of PP2A-B56α is protective against I/R injury and that B56α merits further investigation as a potential therapeutic target.