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<0.01) and accentuated chamber dilation (LVEDV, WT: 63.99+4.82 mm3 vs. −/−: 86.28+4.24 mm3, p<0.01). Increased adverse remodeling in tTG null mice was associated with markedly accentuated cardiomyocyte apoptosis, and with enhanced fibroblast infiltration in the pressure-overloaded myocardium. However, the abundant fibroblasts harvested from pressure-overloaded tTG null hearts were functionally impaired, exhibiting reduced collagen synthesis and defective myofibroblast transdifferentiation. Smad2 phosphorylation was comparable between tTG −/− and WT hearts, suggesting that tTG loss did not affect fibroblast function through impaired activation of the TGF-beta/Smad2 pathway. 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 preventing cardiomyocyte apoptosis, by activating reparative fibroblasts, and by promoting extracellular matrix preservation.
- © 2010 by American Heart Association, Inc.