地昔帕明通过抑制 MAPKs/c-Myc 通路缓解血管紧张素 II 诱导的心脏炎症和重构。
Diacerein alleviates Ang II-induced cardiac inflammation and remodeling by inhibiting the MAPKs/c-Myc pathway.
机构信息
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji 133002, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Cardiology and Medical Research Center, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
出版信息
Phytomedicine. 2022 Nov;106:154387. doi: 10.1016/j.phymed.2022.154387. Epub 2022 Aug 12.
BACKGROUND
Heart failure is a common event in the course of hypertension. Recent studies have highlighted the key role of the non-hemodynamic activity of angiotensin II (Ang II) in hypertension-related cardiac inflammation and remodeling. A naturally occurring compound, diacerein, exhibits anti-inflammatory activities in various systems.
HYPOTHESIS/PURPOSE: In this study, we have examined the potential effects of diacerein on Ang II-induced heart failure.
METHODS
C57BL/6 mice were administered Ang II by micro-osmotic pump infusion for 4 weeks to develop hypertensive heart failure. Mice were treated with diacerein by gavage for final 2 weeks. RNA-sequencing analysis was performed to explore the potential mechanism of diacerein.
RESULTS
We found that diacerein could inhibit inflammation, myocardial fibrosis, and hypertrophy to prevent heart dysfunction, without the alteration of blood pressure. To explore the potential mechanism of diacerein, RNA-sequencing analysis was performed, indicating that MAPKs/c-Myc pathway is involved in that cardioprotective effects of Diacerein. We further confirmed that diacerein inhibits Ang II-activated MAPKs/c-Myc pathway to reduce inflammatory response in mouse hearts and cultured cardiomyocytes. Deficiency of MAPKs or c-Myc in cardiomyocytes abolished the anti-inflammatory effects of diacerein.
CONCLUSION
Our results indicate that diacerein protects hearts in Ang II-induced mice through inhibiting MAPKs/c-Myc-mediated inflammatory responses, rendering diacerein a potential therapeutic candidate agent for hypertensive heart failure.
背景
心力衰竭是高血压病程中的常见事件。最近的研究强调了血管紧张素 II（Ang II）的非血流动力学活性在与高血压相关的心脏炎症和重构中的关键作用。一种天然存在的化合物二乙酰氨己酸具有在各种系统中发挥抗炎作用。
假设/目的：在这项研究中，我们研究了二乙酰氨己酸对 Ang II 诱导的心力衰竭的潜在影响。
方法
通过微渗透泵输注 Ang II 4 周，使 C57BL/6 小鼠发生高血压性心力衰竭。最后 2 周，用二乙酰氨己酸灌胃治疗小鼠。进行 RNA 测序分析以探索二乙酰氨己酸的潜在机制。
结果
我们发现二乙酰氨己酸可抑制炎症、心肌纤维化和肥大，从而防止心脏功能障碍，而不改变血压。为了探索二乙酰氨己酸的潜在机制，进行了 RNA 测序分析，表明 MAPKs/c-Myc 通路参与了二乙酰氨己酸的心脏保护作用。我们进一步证实，二乙酰氨己酸抑制 Ang II 激活的 MAPKs/c-Myc 通路，从而减少小鼠心脏和培养的心肌细胞中的炎症反应。心肌细胞中 MAPKs 或 c-Myc 的缺失消除了二乙酰氨己酸的抗炎作用。
结论
我们的结果表明，二乙酰氨己酸通过抑制 MAPKs/c-Myc 介导的炎症反应来保护 Ang II 诱导的小鼠心脏，使二乙酰氨己酸成为治疗高血压性心力衰竭的潜在治疗候选药物。
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