Abstract 17912: Deficiency of Smad7 Enhances Myocardial Remodeling Induced by Angiotensin II
Purpose: Smad7 is a critical negative regulator of TGF-β/Smad and NF-κB signaling. We have previously shown that disruption of Smad7 function accelerates fibrosis and inflammation in obstructed kidney disease and over expression of Smad7 inhibits fibrosis and inflammation in diabetic kidney injury. However, the protective mechanism of Smad7 in myocardial remodeling remains unclear. Therefore, the present study aimed to investigate the role of Smad7 in cardiac remodeling induced by angiotensin II infusion.
Methods: Hypertensive cardiopathy was induced in both Smad7 knockout (KO) and wild-type (WT) mice by subcutaneous infusion of Ang II (1.46mg/kg/day) for 28 days. Blood pressure was measured by the tail-cuff method; cardiac function was detected by echocardiography. Cardiac fibrosis and inflammation were examined by real-time PCR, western blotting and immunohistochemistry.
Results: Although equal levels of high blood pressure were developed in both Smad7 KO and WT mice, Smad7 KO mice developed more severe cardiac injury as demonstrated by impaired cardiac function including a significant increase in left ventricular (LV) mass (P<0.01) and reduction of LV ejection fraction (P<0.001). Real-time PCR, western blot and immunohistochemistry detected that deletion of Smad7 significantly enhanced Ang II-induced cardiac fibrosis and inflammation, including upregulation of collagen I, α-SMA, proinflammatory cytokines (interleukin-1β, tumor necrosis factor-α), and CD3+ T cells and F4/80+ macrophages (all p<0.05, compared to Smad7 WT mice respectively). These changes were associated with enhanced activation of TGF-β /Smad and NF-κB signaling pathways.
Conclusion: Deficiency of Smad7 enhances fibrosis and inflammation in Ang II-induced hypertensive cardiac remodeling by enhancing activation of TGF-β/Smad and NF-κB signaling pathways. Results from this study reveal that Smad7 plays a protective role in AngII-mediated hypertensive cardiac remodeling and suggest that Smad7 may be a novel therapeutic agent for hypertensive cardiovascular disease.
- © 2012 by American Heart Association, Inc.