2009 Southern Regional Meeting Abstracts

Purpose of Study: We hypothesized that myocardial ischemia causes a decrease in activity of protein phosphatase 2a (PP2a) which increases the phosphorylation of phospholamban (PLB), a protein important for cellular Ca2+ homeostasis, myocardial function, and health.
Methods Used: To show that myocardial ischemia resulted in an decrease in activity of PP2a and an increase in phosphorylation of PLB, we subjected isolated hearts to ischemia and varying periods of reperfusion, and determined PP2a activity and the phosphorylation state of the PP2a target protein PLB. Ischemia reduced PP2a activity by 40% and significantly increased the phosphorylation of PLB in the heart. To establish that a decrease in PP2a, independent of kinases, alters phosphorylation and initiates a beneficial effect, we selectively reduced PP2a activity prior to stressing the hearts. To do this we exposed adult rat hearts to concentrations of okadaic acid (OKA) or S-adenosyl-homocysteine (SAH) to demethylate the catalytic subunit of PP2a (PP2aC) and decrease PP2a activity.
Summary of Results: Pre-exposure with both OKA and SAH significantly reduced the methylation state of PP2a prior to induced ischemia and lead to increased percent functional recoveries in post-ischemic hearts. These results are consistent with the idea that ischemia-induced reductions in PP2a activity through reversible demethylation is an endogenous protective mechanism in the heart.
Conclusions: Treatment with drugs that reduce the activity of PP2a through demethylation may be clinically useful to improve cardiac outcomes if given prior to transient ischemia due to bypass surgery or chemotherapy.