Phospholipase C ε Modulates β-Adrenergic Receptor– Dependent Cardiac Contraction and Inhibits Cardiac Hypertrophy

Abstract

Phospholipase C (PLC) ε is a recently identified enzyme regulated by a wide range of molecules including Ras family small GTPases, Rho A, Gα_12/13, and Gβγ with primary sites of expression in the heart and lung. In a screen for human signal transduction genes altered during heart failure, we found that PLCε mRNA is upregulated. Two murine models of cardiac hypertrophy confirmed upregulation of PLCε protein expression or PLCε RNA. To identify a role for PLCε in cardiac function and pathology, a PLCε-deficient mouse strain was created. Echocardiography indicated PLCε^−/− mice had decreased cardiac function, and direct measurements of left ventricular contraction demonstrated that PLCε^−/− mice had a decreased contractile response to acute isoproterenol administration. Cardiac myocytes isolated from PLCε^−/− mice had decreased β-adrenergic receptor (βAR)-dependent increases in Ca²⁺ transient amplitudes, likely accounting for the contractile deficiency in vivo. This defect appears to be independent from the ability of the βAR system to produce cAMP and regulation of sarcoplasmic reticulum Ca²⁺ pool size. To address the significance of these functional deficits to cardiac pathology, PLCε^−/− mice were subjected to a chronic isoproterenol model of hypertrophic stress. PLCε^−/− mice were more susceptible than wild-type littermates to development of hypertrophy than wild-type littermates. Together, these data suggest a novel PLC-dependent component of βAR signaling in cardiac myocytes responsible for maintenance of maximal contractile reserve and loss of PLCε signaling sensitizes the heart to development of hypertrophy in response to chronic cardiac stress.