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GPR40-Full Agonist AM1638 Alleviates Palmitate-induced Oxidative Damage in H9c2 Cells via an AMPK-dependent Pathway
SukHwan Yun1 (MS), Joo Won Kim1 (PhD), Min Jeong Park2 (MD), Eyun Song2 (MD, PhD), Soo Yeon Jang2 (MD), Ahreum Jang2 (MD), Kyung Mook Choi2 (MD, PhD), Sei Hyun Baik2 (MD, PhD), Hwan-Jin Hwang 1,* (PhD), Hye Jin Yoo 2 (MD, PhD)
1BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea,
2Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
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.
Abstract, Accepted Manuscript [Submitted on March 25, 2024, Accepted on July 4, 2024]
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