Treatment of Hypertensive Heart Disease by Targeting Smad3 Signaling in Mice

Molecular Therapy: Methods & Clinical Development

Lihua Wei¹  Xiyong Yu²  Yuyan Qin²  Xiao-ru Huang³  Hui-yao Lan⁴  Jinxiu Meng⁵  Junzhe Chen⁶ 

[1] Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences &Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China;the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China;Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China;Guangdong Provincial Key Laboratory of Coronary Heart Disease, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China;;Key Laboratory of Molecular Target &

关键词: Ang II;    TGF-β/Smad;    SIS3;    hypertension;    cardiac fibrosis and inflammation;   

DOI  :  

来源: DOAJ

【 摘 要 】

Transforming growth factor β (TGF-β)/Smad3 signaling plays a central role in chronic heart disease. Here, we report that targeting Smad3 with a Smad3 inhibitor SIS3 in an established mouse model of hypertension significantly improved cardiac dysfunctions by preserving the left ventricle (LV) ejection fraction (LVEF) and LV fractional shortening (LVFS), while reducing the LV mass. In addition, SIS3 treatment also halted the progression of myocardial fibrosis by blocking α-smooth muscle actin-positive (α-SMA+) myofibroblasts and collagen matrix accumulation, and inhibited cardiac inflammation by suppressing interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP1), intercellular cell adhesion molecule-1 (ICAM1) expression, and infiltration of CD3+ T cells and F4/80+ macrophages. Interestingly, treatment with SIS3 did not alter levels of high blood pressure, revealing a blood pressure-independent cardioprotective effect of SIS3. Mechanistically, treatment with SIS3 not only directly inactivated TGF-β/Smad3 signaling but also protected cardiac Smad7 from Smurf2-mediated proteasomal ubiquitin degradation. Because Smad7 functions as an inhibitor for both TGF-β/Smad and nuclear factor κB (NF-κB) signaling, increased cardiac Smad7 could be another mechanism through which SIS3 treatment blocked Smad3-mediated myocardial fibrosis and NF-κB-driven cardiac inflammation. In conclusion, SIS3 is a therapeutic agent for hypertensive heart disease. Results from this study demonstrate that targeting Smad3 signaling with SIS3 may be a novel and effective therapy for chronic heart disease.

【 授权许可】

Unknown