The activity of the early signaling enzyme, phospholipase Cβ1b (PLCβ1b), is selectively elevated in diseased myocardium and activity increases with disease progression. We aimed to establish the contribution of heightened PLCβ1b activity to cardiac pathology. PLCβ1b, the alternative splice variant, PLCβ1a, and a blank virus were expressed in mouse hearts using adeno-associated viral vectors (rAAV6-FLAG-PLCβ1b, rAAV6-FLAG-PLCβ1a, or rAAV6-blank) delivered intravenously (IV). Following viral delivery, FLAG-PLCβ1b was expressed in all of the chambers of the mouse heart and was localized to the sarcolemma. Heightened PLCβ1b expression caused a rapid loss of contractility, 4-6weeks, that was fully reversed, within 5days, by inhibition of protein kinase Cα (PKCα). PLCβ1a did not localize to the sarcolemma and did not affect contractile function. Expression of PLCβ1b, but not PLCβ1a, caused downstream dephosphorylation of phospholamban and depletion of the Ca2+ stores of the sarcoplasmic reticulum. We conclude that heightened PLCβ1b activity observed in diseased myocardium contributes to pathology by PKCα-mediated contractile dysfunction. PLCβ1b 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.
- Cardiac contractility
- Gene therapy
- Signaling pathways
Ian Harper (Manager), Stephen Firth (Manager), Alex Fulcher (Operator), Oleks Chernyavskiy (Operator), Margaret Rzeszutek (Other), David Potter (Manager), Volker Hilsenstein (Operator), Juan Nunez-Iglesias (Other), Stephen Cody (Manager), Irena Carmichael (Operator), Betty Kouskousis (Other), Chad Johnson (Operator), Sarah Creed (Manager) & Giulia Ballerin (Operator)Office of the Vice-Provost (Research and Research Infrastructure)