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(Circulation Research. 2003;92:1153.)
© 2003 American Heart Association, Inc.

Integrative Physiology

COX-2–Dependent Cardiac Failure in Gh/tTG Transgenic Mice

Zhibing Zhang, Roberta Vezza, Theodore Plappert, Peter McNamara, John A. Lawson, Sandra Austin, Domenico Praticò, Martin St-John Sutton, Garret A. FitzGerald

From the Center for Experimental Therapeutics (Z.Z., R.V., P.M., J.A.L., S.A., D.P., G.A.F.), University of Pennsylvania School of Medicine, Philadelphia, Pa; and the Division of Cardiovascular Medicine (M.S.S.), University of Pennsylvania School of Medicine Philadelphia, Pa.

Correspondence to Garret A. FitzGerald, MD, Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104-6084. E-mail garret{at}spirit.gcrc.upenn.edu

Gh is a GTP binding protein that couples to the thromboxane receptor (TP), but also functions as tissue transglutaminase II (tTG). A transgenic mouse model was generated in which Gh was overexpressed (GhOE) in ventricular myocytes under the control of the -myosin heavy chain promoter. Heart rate was elevated and both blood pressure and left ventricular ejection fraction were depressed in GhOEs. Left ventricular mass was increased, consistent with genetic and ultrastructural evidence of hypertrophy. Fibrosis and apoptosis were also augmented. Survival declined disproportionately in older GhOEs. Cardiomyocyte expression of COX-2, thromboxane synthase (TxS), and the receptors for TxA₂ (the TP), PGF₂ (the FP), and PGI₂ (the IP) were upregulated and urinary 8,12-iso-iPF₂-VI,2,3-dinor-6-keto-PGF₁ and 2,3-dinor-thromboxane B₂ were increased in GhOEs, reflecting increased lipid peroxidation and cyclooxygenase (COX) activation. Selective COX-2 inhibition, TP antagonism, and suppression of lipid peroxidation each rescued the cardiac phenotype. Infusion of an FP agonist exacerbated the phenotype, whereas administration of an IP agonist improved cardiac function. Directed cardiac overexpression of Gh/tTG causes both TG activation and increased TP/Gh-dependent signaling. The COX-2–dependent increase in TxA₂ generation augments cardiac hypertrophy, whereas formation of PGI₂ by the same isozyme ameliorates the phenotype. Oxidant stress may contribute, via regulation of COX-2 expression and/or ligation of the TP and the FP by isoprostanes. Gh/tTG activation regulates expression of COX-2 and its products may differentially modulate cardiomyocyte commitment to cell death or survival.

Key Words: cardiomyocytes • cyclooxygenase • thromboxane • tissue transglutaminase • G proteins

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