Ramelteon alleviates myocardial ischemia/reperfusion injury (MIRI) through Sirt3--dependent regulation of cardiomyocyte apoptosis

被引:8
作者
Yang, Zhenbo [1 ,2 ]
Xie, Yilin [3 ]
Li, Mengyang [1 ]
Chen, Wenxian [1 ]
Zhong, Changsheng [1 ]
Ju, Jin [2 ]
Deng, Qin [4 ]
Wang, Huifang [1 ]
Cheng, Ting [1 ]
Zhang, Lei [1 ]
Du, Weijie [5 ,6 ]
Liang, Haihai [7 ,8 ]
机构
[1] Shenzhen Univ, Shenzhen Univ Med Sch, Sch Pharm, Shenzhen 518055, Guangdong, Peoples R China
[2] Jinan Univ, Affiliated Hosp 1, Acad Cooperat Lab Basic & Translat Res Chron Dis, Dept Nephrol, Guangzhou, Guangdong, Peoples R China
[3] Shenzhen Univ, Shenzhen Univ Med Sch, Sch Publ Hlth, Shenzhen 518055, Guangdong, Peoples R China
[4] Shenzhen Univ, Shenzhen Univ Med Sch, Sch Basic Med Sci, Shenzhen 518055, Guangdong, Peoples R China
[5] Harbin Med Univ, Coll Pharm,Minist Educ, Dept Pharmacol,Key Lab Cardiovasc Res, State Prov Key Labs Biomed Pharmaceut China, Harbin 150081, Peoples R China
[6] Chinese Acad Med Sci, Res Unit Noninfect Chron Dis Frigid Zone 2019RU070, Harbin 150081, Peoples R China
[7] Jinan Univ, Zhuhai Hosp Affiliated, Zhuhai Peoples Hosp, Guangdong Prov Key Lab Tumor Intervent Diag & Trea, Zhuhai 519000, Guangdong, Peoples R China
[8] Harbin Med Univ, Coll Pharm,Minist Educ,Key Lab Cardiovasc Res, Dept Pharmacol,State Prov Key Labs Biomed Pharmace, State Key Lab Frigid Zone Cardiovasc Dis SKLFZCD, Harbin 150081, Peoples R China
基金
中国国家自然科学基金;
关键词
Ramelteon; Myocardial ischemia/reperfusion injury; Sirt3; Cardiomyocyte apoptosis; REPERFUSION; INSOMNIA; DOCKING;
D O I
10.1016/j.biopha.2024.116229
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Reperfusion stands as a pivotal intervention for ischemic heart disease. However, the restoration of blood flow to ischemic tissue always lead to further damage, which is known as myocardial ischemia/reperfusion injury (MIRI). Ramelteon is an orally administered drug used to improve sleep quality, which is famous for its high bioadaptability and absence of notable addictive characteristics. However, the specific mechanism by which it improves MIRI is still unclear. Sirtuin-3 (Sirt3), primarily located in mitochondria, is crucial in mitigating many cardiac diseases, including MIRI. Based on the structure of Sirt3, we simulated molecular docking and identified several potential amino acid binding sites between it and ramelteon. Therefore, we propose a hypothesis that ramelteon may exert cardioprotective effects by activating the Sirt3 signaling pathway. Our results showed that the activation levels and expression level of Sirt3 were significantly decreased in MIRI tissue and H2O2 stimulated H9C2 cells, while ramelteon treatment upregulated Sirt3 activity and expression. After treat with 3-TYP, a classic Sirt3 activity inhibitor, we constructed myocardial ischemia/reperfusion surgery in vivo and induced H9C2 cells with H2O2 in vitro. The results showed that the myocardial protection and anti-apoptotic effects of ramelteon were antagonized by 3-TYP, indicating that the activation of Sirt3 is a key mechanism for ramelteon to exert myocardial protection. In summary, our results confirm a novel mechanism by which ramelteon improves MIRI by activating Sirt3 signaling pathway, providing strong evidence for the treatment of MIRI with ramelteon.
引用
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页数:10
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