Potential Treatment of Cardiac Hypertrophy and Heart Failure by Inhibiting the Sarcolemmal Binding of Phospholipase Cβ1b

Heart failure, the common end-point of many cardiac diseases, is a major contributor to mortality and morbidity and contributes considerably to health care costs. Current treatment regimens include beta-adrenergic antagonists, angiotensin converting enzyme inhibitors, and inotropic agents are used by some patients. Studies in experimental animals have demonstrated that inhibition of signaling pathways downstream of the heterotrimeric G protein Gq reduces ventricular hypertrophy and protects from the development of heart failure. However, targets identified, to date, have been limited by a lack of tissue specificity. In cardiomyocytes, Gq activates only one splice variant of one subtype of phospholipase C beta, specifically phospholipase C beta 1b (PLC beta 1b) and PLC beta 1b is responsible for Gq mediated hypertrophic and apoptotic responses. PLC beta 1b targets the sarcolemma via its unique C-terminal sequence and its activation can be inhibited by expressing the C-terminal sequence to compete for sarcolemmal binding. Inhibition of PLC beta 1b by the C-terminal peptide reduces hypertrophic responses in cardiomyocytes. We present the evidence that inhibition of the sarcolemmal association of PLC beta 1b provides a cardiac-specific target for the development of drugs to reduce pathological cardiac hypertrophy and thereby to reduce the burden of heart failure.