Treatment of Hypertensive Heart Disease by Targeting Smad3 Signaling in Mice
Autor: | Lihua Wei, Junzhe Chen, Xiao-Ru Huang, Xi-Yong Yu, Yu-Yan Qin, Jinxiu Meng, Hui-Yao Lan |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
hypertension lcsh:QH426-470 Inflammation SMAD Pharmacology Article 03 medical and health sciences 0302 clinical medicine Genetics medicine lcsh:QH573-671 TGF-β/Smad Molecular Biology Ejection fraction integumentary system lcsh:Cytology business.industry SIS3 Interleukin medicine.disease Hypertensive heart disease Ang II lcsh:Genetics 030104 developmental biology cardiac fibrosis and inflammation 030220 oncology & carcinogenesis Molecular Medicine Myocardial fibrosis Tumor necrosis factor alpha medicine.symptom business Transforming growth factor |
Zdroj: | Molecular Therapy. Methods & Clinical Development Molecular Therapy: Methods & Clinical Development, Vol 18, Iss, Pp 791-802 (2020) |
ISSN: | 2329-0501 |
Popis: | 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. Graphical Abstract Meng and colleagues developed a novel and effective therapy for hypertensive heart disease by specifically targeting Smad3, a key mediator of downstream TGF-β signaling, with a Smad3 inhibitor SIS3. They found that SIS3 treatment significantly improved cardiac dysfunctions and suppressed myocardial fibrosis and inflammation in an established mouse model of hypertension. |
Databáze: | OpenAIRE |
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