Phospholipase C (cid:1) Modulates (cid:2) -Adrenergic Receptor Dependent Cardiac Contraction and Inhibits Cardiac Hypertrophy

Phospholipase C (PLC) &egr; is a recently identified enzyme regulated by a wide range of molecules including Ras family small GTPases, Rho A, G&agr;12/13, and G&bgr;&ggr; 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&egr; mRNA is upregulated. Two murine models of cardiac hypertrophy confirmed upregulation of PLC&egr; protein expression or PLC&egr; RNA. To identify a role for PLC&egr; in cardiac function and pathology, a PLC&egr;-deficient mouse strain was created. Echocardiography indicated PLC&egr;−/− mice had decreased cardiac function, and direct measurements of left ventricular contraction demonstrated that PLC&egr;−/− mice had a decreased contractile response to acute isoproterenol administration. Cardiac myocytes isolated from PLC&egr;−/− mice had decreased &bgr;-adrenergic receptor (&bgr;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 &bgr;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&egr;−/− mice were subjected to a chronic isoproterenol model of hypertrophic stress. PLC&egr;−/− 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 &bgr;AR signaling in cardiac myocytes responsible for maintenance of maximal contractile reserve and loss of PLC&egr; signaling sensitizes the heart to development of hypertrophy in response to chronic cardiac stress.

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