RESUMO
The activity of the early signaling enzyme, phospholipase Cß1b (PLCß1b), is selectively elevated in diseased myocardium and activity increases with disease progression. We aimed to establish the contribution of heightened PLCß1b activity to cardiac pathology. PLCß1b, the alternative splice variant, PLCß1a, and a blank virus were expressed in mouse hearts using adeno-associated viral vectors (rAAV6-FLAG-PLCß1b, rAAV6-FLAG-PLCß1a, or rAAV6-blank) delivered intravenously (IV). Following viral delivery, FLAG-PLCß1b was expressed in all of the chambers of the mouse heart and was localized to the sarcolemma. Heightened PLCß1b expression caused a rapid loss of contractility, 4-6 weeks, that was fully reversed, within 5 days, by inhibition of protein kinase Cα (PKCα). PLCß1a did not localize to the sarcolemma and did not affect contractile function. Expression of PLCß1b, but not PLCß1a, caused downstream dephosphorylation of phospholamban and depletion of the Ca(2+) stores of the sarcoplasmic reticulum. We conclude that heightened PLCß1b activity observed in diseased myocardium contributes to pathology by PKCα-mediated contractile dysfunction. PLCß1b is a cardiac-specific signaling system, and thus provides a potential therapeutic target for the development of well-tolerated inotropic agents for use in failing myocardium.