Phospholipase C ε modulates β-adrenergic receptor dependent cardiac contraction and inhibits cardiac hypertrophy

Phospholipase C (PLC) is an element of is a recently identified enzyme regulated by a wide range of molecules including Ras family small GTPases, Rho A, G alpha(12/13), and G beta gamma 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 PLC is an element of mRNA is upregulated. Two murine models of cardiac hypertrophy confirmed upregulation of PLC is an element of protein expression or PLC is an element of RNA. To identify a role for PLC is an element of in cardiac function and pathology, a PLC is an element of-deficient mouse strain was created. Echocardiography indicated PLC is an element of(-/-) mice had decreased cardiac function, and direct measurements of left ventricular contraction demonstrated that PLC is an element of(-/-) mice had a decreased contractile response to acute isoproterenol administration. Cardiac myocytes isolated from PLC is an element of(-/-) mice had decreased beta-adrenergic receptor (beta AR)-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 beta AR system to produce cAMP and regulation of sarcoplasmic reticulum Ca2+ pool size. To address the significance of these functional deficits to cardiac pathology, PLC is an element of(-/-) mice were subjected to a chronic isoproterenol model of hypertrophic stress. PLC is an element of(-/-) 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 beta AR signaling in cardiac myocytes responsible for maintenance of maximal contractile reserve and loss of PLC is an element of signaling sensitizes the heart to development of hypertrophy in response to chronic cardiac stress.