Abstract 20342: Endogenous Tissue Transglutaminase Protects the Pressure-Overloaded Myocardium from Dilative Remodeling by Activating Fibroblasts and by Promoting Matrix Preservation

Tissue transglutaminase (tTG) is a multifunctional protein that modulates inflammatory and reparative pathways by activating TGF-β, by enhancing fibroblast responses to growth factors, by regulating matrix metabolism and by inducing matrix cross-linking. tTG is markedly upregulated during the transition from hypertrophy to heart failure; however, its role in cardiac remodeling remains unknown. We hypothesized that tTG may be critically involved in the fibrotic cardiomyopathy associated with pressure overload. tTG null mice and corresponding wildtype (WT) controls underwent transverse aortic constriction (TAC) protocols. tTG mRNA and protein was markedly upregulated in the pressure-overloaded myocardium; flow cytometry suggested that collagen I+ fibroblasts and CD45+ leukocytes harvested from pressure-overloaded hearts exhibited externalization of tTG on the cell surface. In the absence of injury WT and tTG null mice had comparable cardiac dimensions and function. However after 28 days of TAC tTG −/− mice exhibited markedly increased left ventricular hypertrophy (LV mass, WT: 127.13+6.73 mg vs. −/−: 195.7+12.39 mg, p