Abstract 16231: Endogenous TSP-1 Modulates the Hypertrophic and Fibrotic Response in the Pressure-Overloaded Heart
The matricellular protein Thrombospondin (TSP)-1 is expressed following tissue injury and may regulate reparative responses by activating TGF-β, by suppressing angiogenesis, and by modulating inflammation and matrix metabolism. We hypothesized that TSP-1 induction in the pressure-overloaded heart may regulate cardiac remodeling through effects on cardiomyocytes and interstitial cells. Cardiac TSP-1 expression was increased in a mouse model of pressure overload due to transverse aortic constriction (TAC). TSP-1 −/− mice exhibited increased early hypertrophy(LV mass, WT: 104.9+6.7 mg vs. −/−:134.1+10.8 mg, p<0.05) and enhanced late dilation (LVEDD, WT: 3.79+0.15 mm vs. −/−:4.24+0.13mm , p<0.05). in response to pressure overload. Pressure-overloaded TSP-1 null mice had intense degenerative cardiomyocyte changes, exhibiting extensive sarcomeric loss and sarcolemmal disruption, and markedly increased density of apoptotic cells when compared with WT hearts. Accentuated cardiomyocyte loss in TSP-1 −/− hearts was accompanied by increased myofibroblast density. However, despite a two-fold higher infiltration of the cardiac interstitium with myofibroblasts, pressure-overloaded TSP-1 null hearts did not exhibit significantly increased collagen content when compared with WT hearts. Immunofluorescence and flow cytometry demonstrated that fibroblasts harvested from pressure-overloaded TSP-1 null hearts, had impaired myofibroblast differentiation and reduced collagen expression in comparison to WT fibroblasts. Impaired myofibroblast activation in TSP-1 null hearts was associated with reduced Smad2 phosphorylation reflecting defective TGF-β signaling. Moreover, TSP-1 null hearts had increased myocardial Matrix Metalloproteinase (MMP)-3 expression and enhanced MMP-9 activation following pressure overload. TSP-1 upregulation in the pressure-overloaded heart protects cardiomyocytes from apoptosis, induces TGF-β-mediated myofibroblast activation and promotes matrix preservation. TSP-1 deposition in the cardiac interstitium may serve as a protective “shield” preventing adverse remodeling of the pressure-overloaded heart.
- © 2010 by American Heart Association, Inc.