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.
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.
Circ Res. 2020 Apr 10;126(8):1007-1023. doi: 10.1161/CIRCRESAHA.119.315861. Epub 2020 Feb 26.
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.
We have examined the potential effect of celastrol-a bioactive compound derived from the Celastraceae family-on Ang II-induced cardiac dysfunction.
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.
Our studies show that celastrol inhibits Ang II-induced cardiac dysfunction by inhibiting STAT3 activity.
过量的血管紧张素 II（血管紧张素 II）水平导致致纤维化和肥大环境，从而在高血压相关心力衰竭中产生有害的重塑和功能障碍。破坏血管紧张素 II 诱导的心脏功能障碍的药物可能在治疗高血压相关心力衰竭方面具有临床应用价值。
我们研究了从卫矛科植物中提取的生物活性化合物 celastrol 对血管紧张素 II 诱导的心脏功能障碍的潜在影响。
在大鼠原代心肌细胞和 H9C2（大鼠心肌细胞样 H9C2）细胞中，celastrol 可减轻血管紧张素 II 诱导的细胞肥大和纤维化反应。利用蛋白质组微阵列、表面等离子体共振、竞争结合测定和分子模拟来鉴定 celastrol 的分子靶标。我们的数据表明，celastrol 直接结合并抑制 STAT（信号转导和转录激活因子）-3 的磷酸化和核转位。功能测试表明，celastrol 的保护作用是通过靶向 STAT3 实现的。STAT3 的过表达通过部分挽救 STAT3 活性来减弱 celastrol 的作用。最后，我们研究了 celastrol 治疗在血管紧张素 II 挑战和主动脉缩窄模型中挑战的小鼠体内的效果。我们表明，celastrol 通过抑制心脏纤维化和肥大来保护血管紧张素 II 挑战和主动脉缩窄挑战小鼠的心脏功能。
我们的研究表明，celastrol 通过抑制 STAT3 活性抑制血管紧张素 II 诱导的心脏功能障碍。
