Exendin-4 exhibits cardioprotective effects against high glucose-induced mitochondrial abnormalities: Potential role of GLP-1 receptor and mTOR signaling

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2024-09-20 DOI:10.1016/j.bcp.2024.116552

Warisara Parichatikanond , Sudhir Pandey , Supachoke Mangmool

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Abstract

Mitochondrial dysfunction is associated with hyperglycemic conditions and insulin resistance leading to cellular damage and apoptosis of cardiomyocytes in diabetic cardiomyopathy. The dysregulation of glucagon-like peptide-1 (GLP-1) receptor and mammalian target of rapamycin (mTOR) is linked to cardiomyopathies and myocardial dysfunctions mediated by hyperglycemia. However, the involvements of mTOR for GLP-1 receptor-mediated cardioprotection against high glucose (HG)-induced mitochondrial disturbances are not clearly identified. The present study demonstrated that HG-induced cellular stress and mitochondrial damage resulted in impaired ATP production and oxidative defense markers such as catalase and SOD2, along with a reduction in survival markers such as Bcl-2 and p-Akt, while an increased expression of pro-apoptotic marker Bax was observed in H9c2 cardiomyoblasts. In addition, the autophagic marker LC3-II was considerably reduced, together with the disruption of autophagy regulators (p-mTOR and p-AMPKα) under the hyperglycemic state. Furthermore, there was a dysregulated expression of several indicators related to mitochondrial homeostasis, including MFN2, p-DRP1, FIS1, MCU, UCP3, and Parkin. Remarkably, treatment with either exendin-4 (GLP-1 receptor agonist) or rapamycin (mTOR inhibitor) significantly inhibited HG-induced mitochondrial damage while co-treatment of exendin-4 and rapamycin completely reversed all mitochondrial abnormalities. Antagonism of GLP-1 receptors using exendin-(9–39) abolished these cardioprotective effects of exendin-4 and rapamycin under HG conditions. In addition, exendin-4 attenuated HG-induced phosphorylation of mTOR, and this inhibitory effect was antagonized by exendin-(9–39), indicating the regulation of mTOR by GLP-1 receptor. Therefore, improvement of mitochondrial dysfunction by stimulating the GLP-1 receptor/AMPK/Akt pathway and inhibiting mTOR signaling could ameliorate cardiac abnormalities caused by hyperglycemic conditions.

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Exendin-4 对高血糖诱导的线粒体异常具有心脏保护作用：GLP-1 受体和 mTOR 信号转导的潜在作用

线粒体功能障碍与高血糖和胰岛素抵抗有关，导致糖尿病心肌病中心肌细胞的细胞损伤和凋亡。胰高血糖素样肽-1（GLP-1）受体和哺乳动物雷帕霉素靶标（mTOR）的失调与高血糖介导的心肌病和心肌功能障碍有关。然而，mTOR 在 GLP-1 受体介导的心脏保护中对高糖（HG）诱导的线粒体紊乱的参与尚未明确。本研究表明，HG 诱导的细胞应激和线粒体损伤导致 ATP 生成和氧化防御标志物（如过氧化氢酶和 SOD2）受损，生存标志物（如 Bcl-2 和 p-Akt）减少，同时在 H9c2 心肌细胞中观察到促凋亡标志物 Bax 的表达增加。此外，在高血糖状态下，自噬标记物 LC3-II 显著减少，自噬调节因子（p-mTOR 和 p-AMPKα）也受到破坏。此外，与线粒体平衡相关的一些指标（如 MFN2、p-DRP1、FIS1、MCU、UCP3 和 Parkin）的表达也出现失调。值得注意的是，用外显子-4（GLP-1 受体激动剂）或雷帕霉素（mTOR 抑制剂）治疗可显著抑制 HG 诱导的线粒体损伤，而外显子-4 和雷帕霉素联合治疗可完全逆转所有线粒体异常。在 HG 条件下，使用 exendin-（9-39）拮抗 GLP-1 受体可消除 exendin-4 和雷帕霉素的这些心脏保护作用。此外，exendin-4 可减轻 HG 诱导的 mTOR 磷酸化，exendin-（9-39）可拮抗这种抑制作用，表明 GLP-1 受体可调节 mTOR。因此，通过刺激 GLP-1 受体/AMPK/Akt 通路和抑制 mTOR 信号转导来改善线粒体功能障碍，可以改善高血糖条件下引起的心脏异常。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.