Abstract 16613: Endogenous Tissue Transglutaminase Protects the Pressure-Overloaded Myocardium From Dilative Remodeling by Preserving Matrix Integrity
Tissue transglutaminase (tTG) is a multifunctional protein that modulates inflammation and repair 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 in failing hearts; however, its role in cardiac remodeling remains unknown. In order to examine whether tTG is involved in the fibrotic cardiomyopathy associated with pressure overload we performed transverse aortic constriction (TAC) protocols in tTG null and wildtype (WT) mice. 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 28d of TAC, tTG -/- mice exhibited increased LV hypertrophy (LV mass, WT: 127.13+6.73 mg vs. -/-: 195.7+12.39 mg, p<0.01) and accentuated chamber dilation (LVEDV, WT: 63.99+4.82 mm3 vs. -/-: 86.28+4.24 mm3, p<0.01). WT and tTG -/- pressure-overloaded hearts had comparable numbers of apoptotic cardiomyocytes indicating that accentuated remodeling observed in -/- animals cannot be explained by increased cell loss. Increased adverse remodeling in tTG -/- mice was associated with enhanced fibroblast infiltration in the pressure-overloaded myocardium. WT and null fibroblasts isolated from pressure overloaded hearts displayed similar collagen and a-SMA expression and comparable responses to TGF-beta. A collagen crosslinking assay demonstrated that deposition of insoluble collagen in tTG null hearts was significantly reduced in comparison to WT animals, suggesting that disruption of tTG resulted in markedly impaired collagen crosslinking in response to pressure overload. In addition, zymography showed that tTG null hearts had significantly increased MMP-2 activation indicating that tTG inhibits matrix degradation in the pressure-overloaded ventricle. The findings suggest that tTG exerts protective effects on the pressure-overloaded myocardium by crosslinking of collagen and by preventing excessive matrix degradation.
- © 2011 by American Heart Association, Inc.