title: COX-2-dependent cardiac failure in Gh/tTG transgenic mice.
abstract: 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 alpha-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), PGF2alpha (the FP), and PGI2 (the IP) were upregulated and urinary 8,12-iso-iPF2alpha-VI,2,3-dinor-6-keto-PGF1alpha 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.
authors.affiliation: Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pa 19104-6084, USA.
authors.forename: Zhibing
authors.initials: Z
authors.lastname: Zhang
authors.forename: Roberta
authors.initials: R
authors.lastname: Vezza
authors.forename: Theodore
authors.initials: T
authors.lastname: Plappert
authors.forename: Peter
authors.initials: P
authors.lastname: McNamara
authors.forename: John A
authors.initials: JA
authors.lastname: Lawson
authors.forename: Sandra
authors.initials: S
authors.lastname: Austin
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
authors.forename: Martin St-John
authors.initials: MS
authors.lastname: Sutton
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D019204:GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis / Q000494:pharmacology / Q000652:urine; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D013318:Stroke Volume / Q000187:drug effects / Q000235:genetics; D015996:Survival Rate; D013930:Thromboxane-A Synthase / Q000096:biosynthesis; D011503:Transglutaminases / Q000096:biosynthesis* / Q000235:genetics; D024723:Ventricular Myosins / Q000235:genetics
chemical_list: D007527:Isoenzymes; D011453:Prostaglandins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D024723:Ventricular Myosins; D013930:Thromboxane-A Synthase