GPR40-full agonist AM1638 alleviates palmitate-induced oxidative damage in H9c2 cells via an AMPK-dependent pathway
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G protein-coupled receptor 40 (GPR40) is gaining recognitionas 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 whethertreatment with AM1638, a GPR40-full agonist, reduces palmitate-mediated cell damage in H9c2 rat cardiomyocytes. AM1638treatment increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and expression levelsof the antioxidant molecules heme oxygenase-1 (HO-1) andnicotinamide adenine dinucleotide phosphate: quinone oxidoreductase-1 (NQO1). Palmitate-mediated superoxide productionand levels of 4-hydroxynonenal, a biomarker of oxidative stress,decreased after treatment with AM1638. Notably, palmitate-mediateddisruption of mitochondrial membrane potential, lowerlevels of mitochondrial complex protein, and failure of adenosinetriphosphate production were all recovered by treatmentwith AM1638. Moreover, AM1638 blocked palmitate-mediatedcaspase-3 cleavage and nuclear fragmentation, thereby improvingcell viability. However, these AM1638-mediated beneficialeffects were abrogated by treatment with Compound C, anAMPK inhibitor. These results demonstrate that AM1638, aGPR40-full agonist, ameliorates palmitate-mediated oxidativestress in H9c2 cells in an AMPK-dependent manner.
Abstract
G protein-coupled receptor 40 (GPR40) is gaining recognitionas 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 whethertreatment with AM1638, a GPR40-full agonist, reduces palmitate-mediated cell damage in H9c2 rat cardiomyocytes. AM1638treatment increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and expression levelsof the antioxidant molecules heme oxygenase-1 (HO-1) andnicotinamide adenine dinucleotide phosphate: quinone oxidoreductase-1 (NQO1). Palmitate-mediated superoxide productionand levels of 4-hydroxynonenal, a biomarker of oxidative stress,decreased after treatment with AM1638. Notably, palmitate-mediateddisruption of mitochondrial membrane potential, lowerlevels of mitochondrial complex protein, and failure of adenosinetriphosphate production were all recovered by treatmentwith AM1638. Moreover, AM1638 blocked palmitate-mediatedcaspase-3 cleavage and nuclear fragmentation, thereby improvingcell viability. However, these AM1638-mediated beneficialeffects were abrogated by treatment with Compound C, anAMPK inhibitor. These results demonstrate that AM1638, aGPR40-full agonist, ameliorates palmitate-mediated oxidativestress in H9c2 cells in an AMPK-dependent manner.