Metformin Attenuates Myocardial Ischemia-Reperfusion Injury through the AMPK-HMGCR-ROS Signaling Axis.

IF 0.5 4区医学 Q4 CARDIAC & CARDIOVASCULAR SYSTEMS Kardiologiya Pub Date : 2024-10-31 DOI:10.18087/cardio.2024.10.n2739

He Zhu, Tao Zhu, Dubiao Dubiao, Xinmei Zhang

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Abstract

Objective: To explore the role and mechanism of metformin (MET) in regulating myocardial injury caused by cardiac ischemia-reperfusion.

Material and methods: A rat model of myocardial ischemia-reperfusion injury was established by ligation of the anterior descending branch of the left coronary artery. The myocardial area at risk and the infarction size were measured by Evans blue and 2,3,5‑triphenyltetrazole chloride (TTC) staining, respectively. Terminal Deoxynucleotidyl Transferase-Mediated dUTP Nick End Labeling (TUNEL) staining was used to detect apoptosis of cardiomyocytes. The expression of 4‑hydroxynonenal (4‑HNE) was detected by immunohistochemical staining. Real-time quantitative polymerase chain reaction (RT-PCR) and Western blot were used to detect mRNA and expression of the Adenosine 5'-monophosphate-activated protein kinase (AMPK) - 3‑hydroxy-3‑methylglutaryl-CoA reductase (HMGCR) signaling pathway, respectively.

Results: MET treatment decreased the infarct size and the activity of the myocardial enzyme profile, thus demonstrating protection of ischemic myocardium. The number of TUNEL positive cells significantly decreased. Immunohistochemical results showed that MET decreased the expression of 4‑HNE in myocardial tissue and the content of malondialdehyde (MDA) in myocardial cells. Further experimental results showed that MET decreased HMGCR transcription and protein expression, and increased AMPK phosphorylation. In the model of hypoxia and reoxygenation injury of cardiomyocytes, MET increased the viability of cardiomyocytes, decreased the activity of lactic dehydrogenase (LDH), decreased malondialdehyde content and intracellular reactive oxygen species (ROS) concentrations, and regulate the AMPK-HMGCR signaling pathway through coenzyme C (ComC).

Conclusion: MET inhibits the expression of HMGCR by activating AMPK, reduces oxidative damage and apoptosis of cardiomyocytes, and alleviates myocardial ischemia-reperfusion injury.

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二甲双胍通过 AMPK-HMGCR-ROS 信号轴减轻心肌缺血再灌注损伤

目的材料与方法：通过结扎左冠状动脉前降支，建立大鼠心肌缺血再灌注损伤模型：通过结扎左冠状动脉前降支，建立大鼠心肌缺血再灌注损伤模型。用伊文思蓝和 2,3,5-三苯基氯化四氮唑（TTC）染色法分别测量心肌危险面积和梗死面积。末端脱氧核苷酸转移酶介导的 dUTP 镍端标记（TUNEL）染色用于检测心肌细胞的凋亡。免疫组化染色法检测4-羟基壬烯醛（4-HNE）的表达。实时定量聚合酶链反应（RT-PCR）和 Western 印迹分别用于检测腺苷-5'-单磷酸激活蛋白激酶（AMPK）-3-羟基-3-甲基戊二酰-CoA 还原酶（HMGCR）信号通路的 mRNA 和表达：MET治疗缩小了心肌梗死面积，降低了心肌酶谱的活性，从而显示出对缺血心肌的保护作用。TUNEL阳性细胞数量明显减少。免疫组化结果显示，MET 降低了心肌组织中 4-HNE 的表达和心肌细胞中丙二醛（MDA）的含量。进一步的实验结果表明，MET能降低HMGCR的转录和蛋白表达，增加AMPK的磷酸化。在心肌细胞缺氧和再氧损伤模型中，MET可提高心肌细胞的活力，降低乳酸脱氢酶（LDH）的活性，减少丙二醛含量和细胞内活性氧（ROS）浓度，并通过辅酶C（ComC）调节AMPK-HMGCR信号通路：结论：MET通过激活AMPK抑制HMGCR的表达，减少心肌细胞的氧化损伤和凋亡，减轻心肌缺血再灌注损伤。

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来源期刊

Kardiologiya 医学-心血管系统

CiteScore

1.70

自引率

20.00%

发文量

审稿时长

3-8 weeks

期刊介绍： “Kardiologiya” (Cardiology) is a monthly scientific, peer-reviewed journal committed to both basic cardiovascular medicine and practical aspects of cardiology. As the leader in its field, “Kardiologiya” provides original coverage of recent progress in cardiovascular medicine. We publish state-of-the-art articles integrating clinical and research activities in the fields of basic cardiovascular science and clinical cardiology, with a focus on emerging issues in cardiovascular disease. Our target audience spans a diversity of health care professionals and medical researchers working in cardiovascular medicine and related fields. The principal language of the Journal is Russian, an additional language – English (title, authors’ information, abstract, keywords). “Kardiologiya” is a peer-reviewed scientific journal. All articles are reviewed by scientists, who gained high international prestige in cardiovascular science and clinical cardiology. The Journal is currently cited and indexed in major Abstracting & Indexing databases: Web of Science, Medline and Scopus. The Journal''s primary objectives Contribute to raising the professional level of medical researchers, physicians and academic teachers. Present the results of current research and clinical observations, explore the effectiveness of drug and non-drug treatments of heart disease, inform about new diagnostic techniques; discuss current trends and new advancements in clinical cardiology, contribute to continuing medical education, inform readers about results of Russian and international scientific forums; Further improve the general quality of reviewing and editing of manuscripts submitted for publication; Provide the widest possible dissemination of the published articles, among the global scientific community; Extend distribution and indexing of scientific publications in major Abstracting & Indexing databases.