Rationale: Excessive angiotensin II (Ang II) levels lead to a pro-fibrotic 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 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 signal transducer and activator of transcription-3 (STAT3) 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 (TAC) model. We show that Celastrol administration protected heart function in Ang II- and TAC-challenged mice by inhibiting cardiac fibrosis and hypertrophy. Conclusions: Our studies show that Celastrol inhibits Ang II-induced cardiac dysfunction by inhibiting STAT3 activity.

中文翻译：

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Celastrol 通过靶向 STAT3 减弱血管紧张素 II 诱导的心脏重塑。

基本原理：过多的血管紧张素 II (Ang II) 水平会导致促纤维化和肥大环境，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 Ang II 诱导的心功能不全的药物可能在治疗高血压相关心力衰竭方面具有临床效用。目的：我们已经研究了 Celastrol（一种来自 Celastraceae 家族的生物活性化合物）对 Ang II 诱导的心脏功能障碍的潜在影响。方法和结果：在大鼠原代心肌细胞和 H9C2 细胞中，Celastrol 减弱 Ang II 诱导的细胞肥大和纤维化反应。蛋白质组微阵列、表面等离子共振、竞争性结合测定和分子模拟用于鉴定 Celastrol 的分子靶标。我们的数据表明，Celastrol 直接结合并抑制信号转导和转录激活因子 3 (STAT3) 磷酸化和核转位。功能测试表明，Celastrol 的保护是通过靶向 STAT3 提供的。STAT3 的过表达通过部分挽救 STAT3 活性来抑制 Celastrol 的作用。最后，我们研究了 Celastrol 治疗在受到 Ang II 攻击的小鼠和横向主动脉缩窄 (TAC) 模型中的体内效果。我们表明 Celastrol 给药通过抑制心脏纤维化和肥大来保护 Ang II 和 TAC 攻击的小鼠的心脏功能。结论：我们的研究表明，Celastrol 通过抑制 STAT3 活性来抑制 Ang II 诱导的心功能不全。