Shiju Ye1,2, Wu Luo2, Zia A Khan2, Gaojun Wu1, Lina Xuan3, Peiren Shan1, Ke Lin1,2, Taiwei Chen2, Jingying Wang2, Xiang Hu4, Shengjie Wang3, Weijian Huang1, Guang Liang1,2. 1. From the Department of Cardiology in the First Affiliated Hospital (S.Y., G.W., P.S., K.L., T.C., W.H., G.L.), Wenzhou Medical University, Zhejiang, China. 2. Chemical Biology Research Center in School of Pharmaceutical Sciences (S.Y., W.L., Z.A.K., K.L., T.C., J.W., G.L.), Wenzhou Medical University, Zhejiang, China. 3. Department of Pharmacology at College of Pharmacy (the Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical University, Heilongjiang, China (L.X., S.W.). 4. Department of Endocrinology in the First Affiliated Hospital (X.H.), Wenzhou Medical University, Zhejiang, China.
Abstract
RATIONALE: Excessive Ang II (angiotensin II) levels lead to a profibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II-induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure. OBJECTIVE: We have examined the potential effect of celastrol-a bioactive compound derived from the Celastraceae family-on Ang II-induced cardiac dysfunction. METHODS AND RESULTS: In rat primary cardiomyocytes and H9C2 (rat cardiomyocyte-like H9C2) cells, celastrol attenuates Ang II-induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of celastrol. Our data showed that celastrol directly binds to and inhibits STAT (signal transducer and activator of transcription)-3 phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of celastrol treatment in mice challenged with Ang II and in the transverse aortic constriction model. We show that celastrol administration protected heart function in Ang II-challenged and transverse aortic constriction-challenged mice by inhibiting cardiac fibrosis and hypertrophy. CONCLUSIONS: Our studies show that celastrol inhibits Ang II-induced cardiac dysfunction by inhibiting STAT3 activity.
RATIONALE: Excessive Ang II (angiotensin II) levels lead to a profibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II-induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure. OBJECTIVE: We have examined the potential effect of celastrol-a bioactive compound derived from the Celastraceae family-on Ang II-induced cardiac dysfunction. METHODS AND RESULTS: In rat primary cardiomyocytes and H9C2 (rat cardiomyocyte-like H9C2) cells, celastrol attenuates Ang II-induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of celastrol. Our data showed that celastrol directly binds to and inhibits STAT (signal transducer and activator of transcription)-3 phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of celastrol treatment in mice challenged with Ang II and in the transverse aortic constriction model. We show that celastrol administration protected heart function in Ang II-challenged and transverse aortic constriction-challenged mice by inhibiting cardiac fibrosis and hypertrophy. CONCLUSIONS: Our studies show that celastrol inhibits Ang II-induced cardiac dysfunction by inhibiting STAT3 activity.
Entities:
Keywords:
angiotensin II; heart failure; hypertension; molecular targeted therapy; signal transducer and activator of transcription 3
Authors: Luca Liberale; Lina Badimon; Fabrizio Montecucco; Thomas F Lüscher; Peter Libby; Giovanni G Camici Journal: J Am Coll Cardiol Date: 2022-03-01 Impact factor: 24.094
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