Yun SukHwan, Kim Joo Won, Park Min Jeong, Song Eyun, Jang Soo Yeon, Jang Ahreum, Choi Kyung Mook, Baik Sei Hyun, Hwang Hwan-Jin, Yoo Hye Jin
BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, Korea.
BMB Rep. 2025 Mar;58(3):133-139. doi: 10.5483/BMBRep.2024-0043.
G protein-coupled receptor 40 (GPR40) is gaining recognition as a potential therapeutic target for several metabolic disturbances, such as hyperglycemia and excessive inflammation. GPR40 is expressed in various tissues, including the heart; however, its specific roles in cardiomyocytes remain unknown. The objective of the present study was to investigate whether treatment with AM1638, a GPR40-full agonist, reduces palmitate-mediated cell damage in H9c2 rat cardiomyocytes. AM1638 treatment increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and expression levels of the antioxidant molecules heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase-1 (NQO1). Palmitate-mediated superoxide production and levels of 4-hydroxynonenal, a biomarker of oxidative stress, decreased after treatment with AM1638. Notably, palmitate-mediated disruption of mitochondrial membrane potential, lower levels of mitochondrial complex protein, and failure of adenosine triphosphate production were all recovered by treatment with AM1638. Moreover, AM1638 blocked palmitate-mediated caspase-3 cleavage and nuclear fragmentation, thereby improving cell viability. However, these AM1638-mediated beneficial effects were abrogated by treatment with Compound C, an AMPK inhibitor. These results demonstrate that AM1638, a GPR40-full agonist, ameliorates palmitate-mediated oxidative stress in H9c2 cells in an AMPK-dependent manner. [BMB Reports 2025; 58(3): 133-139].
G蛋白偶联受体40（GPR40）作为几种代谢紊乱（如高血糖和过度炎症）的潜在治疗靶点正逐渐受到认可。GPR40在包括心脏在内的各种组织中均有表达；然而，其在心肌细胞中的具体作用仍不清楚。本研究的目的是调查GPR40完全激动剂AM1638的治疗是否能减少棕榈酸酯介导的H9c2大鼠心肌细胞损伤。AM1638治疗增加了腺苷单磷酸激活蛋白激酶（AMPK）的磷酸化以及抗氧化分子血红素加氧酶-1（HO-1）和烟酰胺腺嘌呤二核苷酸磷酸：醌氧化还原酶-1（NQO1）的表达水平。用AM1638治疗后，棕榈酸酯介导的超氧化物产生以及氧化应激生物标志物4-羟基壬烯醛的水平降低。值得注意的是，棕榈酸酯介导的线粒体膜电位破坏、线粒体复合蛋白水平降低以及三磷酸腺苷生成失败均通过AM1638治疗得到恢复。此外，AM1638阻断了棕榈酸酯介导的半胱天冬酶-3切割和核碎裂，从而提高了细胞活力。然而，用AMPK抑制剂Compound C处理可消除这些AM1638介导的有益作用。这些结果表明，GPR40完全激动剂AM1638以AMPK依赖的方式改善了棕榈酸酯介导的H9c2细胞氧化应激。[《BMB报告》2025；58(3): 133 - 139]
