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(Circulation Research. 2005;97:1305.)
© 2005 American Heart Association, Inc.

Cellular Biology

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

Huan Wang^*, Emily A. Oestreich^*, Naoya Maekawa, Tara A. Bullard, Karen L. Vikstrom, Robert T. Dirksen, Grant G. Kelley, Burns C. Blaxall, Alan V. Smrcka

From the Departments of Pharmacology and Physiology (H.W., E.A.O., R.T.D., B.C.B., A.V.S.) and Biochemistry and Biophysics (H.W., A.V.S.) and the Cardiovascular Research Institute (N.M., T.A.B., B.C.B.), University of Rochester School of Medicine, Rochester, NY; and Departments of Pharmacology (K.L.V., G.G.K.) and Medicine (G.G.K.), State University of New York Upstate Medical University, Syracuse.

Correspondence to Alan V. Smrcka, Department of Pharmacology and Physiology, University of Rochester School of Medicine, 601 Elmwood Ave, Box 711, Rochester, NY 14642. E-mail Alan_Smrcka{at}URMC.rochester.edu

Phospholipase C (PLC) is a recently identified enzyme regulated by a wide range of molecules including Ras family small GTPases, Rho A, G_12/13, and Gß 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 mRNA is upregulated. Two murine models of cardiac hypertrophy confirmed upregulation of PLC protein expression or PLC RNA. To identify a role for PLC in cardiac function and pathology, a PLC-deficient mouse strain was created. Echocardiography indicated PLC^–/– mice had decreased cardiac function, and direct measurements of left ventricular contraction demonstrated that PLC^–/– mice had a decreased contractile response to acute isoproterenol administration. Cardiac myocytes isolated from PLC^–/– mice had decreased ß-adrenergic receptor (ßAR)-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 ßAR system to produce cAMP and regulation of sarcoplasmic reticulum Ca²⁺ pool size. To address the significance of these functional deficits to cardiac pathology, PLC^–/– mice were subjected to a chronic isoproterenol model of hypertrophic stress. PLC^–/– 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 ßAR signaling in cardiac myocytes responsible for maintenance of maximal contractile reserve and loss of PLC signaling sensitizes the heart to development of hypertrophy in response to chronic cardiac stress.

Key Words: phospholipase C • ß-adrenergic receptor • heart failure • contractility

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