Abstract 1219: Counterregulatory Roles of TGF-β and ANP Signaling in Pressure Overload-Induced Cardiac Remodeling and Fibrosis
The current study utilized a novel transgenic mouse model that expresses an inducible dominant-negative mutation of the transforming growth factor (TGF)-β type II receptor (DnTGFβRII) to test the hypothesis that TGF-β signaling plays an important role in the pathogenesis of pressure overload-induced cardiac fibrosis and remodeling. Transverse aortic constriction (TAC) was used to induce pressure overload in the heart. Two distinct control strains were used: nontransgenic (NTG) mice and atrial natriuretic peptide (ANP) null (Nppa−/−) mice, in which the effects of pressure overload resulting in cardiac fibrosis and remodeling were expected to be amplified. Eight to10 wk old male DnTGFβRII mice and NTG mice were given 25 mM ZnSO4 in drinking water 1 wk prior to TAC to induce the expression of DnTGFβRII gene. One wk after TAC, hearts were excised, weighed and processed for histological and immunohistochemical analyses. Quantitative assessment of interstitial collagen content, cell proliferation and apoptosis was performed in picrosirious red, Ki67 and TUNEL stained sections of left ventricle (LV) by light microscopy with a Qimaging system. TAC-induced increases in LV hypertrophy were equal among ZnSO4 and H2O DnTGFβRII and NTG mice, and enhanced in Nppa−/− mice. TAC induced significant increases in nonmyocyte proliferation in LV of all three strains of H2O control mice. This effect was dramatically reduced in ZnSO4 DnTGFβRII mice (Table⇓). TAC increased interstitial collagen content in NTG and Nppa−/− mice (Nppa−/− was greater than NTG), but not in DnTGFβRII mice. The apoptotic activity was low in LV of all treatment/strain groups. These data indicate that induction of DnTGFβRII attenuates nonmyocyte proliferation and fibrosis in LV following TAC, while these responses are exaggerated in Nppa−/−. These results support the hypothesis that endogenous TGF-β and ANP play important counterregulatory roles in pressure overload-induced cardiac remodeling and fibrosis.