Abstract 3771: Blocking of Transforming Growth Factor (TGF)-β Signaling Exacerbates Pressure Overload-induced Left Ventricular Remodeling and Dysfunction
Introduction: We have previously used a novel transgenic mouse model that expresses an inducible dominant negative mutation of the TGF-β type II receptor (DnTGFβRII) to demonstrate that blocking pro-fibrogenic TGF-β signaling reduces pressure overload-induced interstitial collagen deposition in the heart. The current study utilized DnTGFβRII mice to test the hypothesis that collagen deposition in the pressure overloaded heart is required to maintain structure and prevent cardiac dilation and dysfunction.
Methods: 8 –10 wk old male DnTGFβBRII mice and nontransgenic control (NTG) mice were given 25 mM ZnSO4 in drinking water to induce the expression of DnTGFβRII gene 1 wk prior to transverse aortic constriction (TAC). 120 days after TAC or sham operation, left ventricular (LV) mass, dimension and function were assessed by echocardiography using a high frequency ultrasound probe and interstitial collagen content was assessed in picrosirius red stained sections of LV by light microscopy with a Qimaging system.
Results: LV end diastolic and systolic diameters (LVEDD and LVESD) and end diastolic and systolic volumes (EDV and ESV) were significantly increased in Zn++ treated DnTGFβBRII mice after TAC, while ejection fraction (EF=StrokeVolume/EDVx100) and fractional shortening FS=[(LVSDD-LVESD)/LVEDDx100] were significantly decreased in this group compared to the other five treatment groups (Table⇓). The DnTGFβRII group receiving H2O only did not differ from NTG mice in any parameter. TAC induced collagen deposition was significantly attenuated in the TAC-DnTGFβRII+Zn++ mice only.
Conclusion: These data indicate that induction of DnTGFβRII expression attenuates LV fibrosis and promotes cardiac dilation following TAC, and support the hypothesis that intact endogenous TGF-β signaling is required to protect against LV dilation and dysfunction in the presence of pressure overload stress.