Pyrrolidinyl caffeamide against ischemia/reperfusion injury in cardiomyocytes through AMPK/AKT pathways

Abstract

BackgroundCoronary heart disease is a leading cause of death in the world and therapy to reduce injury is still needed. The uncoupling of glycolysis and glucose oxidation induces lactate accumulation during myocardial ischemia/reperfusion (I/R) injury. Cell death occurs and finally leads to myocardial infarction. Caffeic acid, one of the major phenolic constituents in nature, acts as an antioxidant. Pyrrolidinyl caffeamide (PLCA), a new derivative of caffeic acid, was synthesized by our team. We aimed to investigate the effect of PLCA on hypoxia/reoxygenation (H/R) in neonatal rat ventricular myocytes (NRVM) and on myocardial I/R in rats.ResultsCardiomyocytes were isolated and subjected to 6 h hypoxia followed by 18 h reperfusion. PLCA (0.1 to 3 μM) and metformin (30 μM) were added before hypoxia was initiated. PLCA at 1 μM and metformin at 30 μM exerted similar effects on the improvement of cell viability and the alleviation of cell apoptosis in NRVM after H/R. PLCA promoted p-AMPK, p-AKT, and GLUT4 upregulation to induce a cardioprotective effect in both cell and animal model. The accumulation of cardiac lactate was attenuated by PLCA during myocardial I/R, and infarct size was smaller in rats treated with PLCA (1 mg/kg) than in those treated with caffeic acid (1 mg/kg).ConclusionsAMPK and AKT are synergistically activated by PLCA, which lead facilities glucose utilization, thereby attenuating lactate accumulation and cell death. The cardioprotective dose of PLCA was lower than those of metformin and caffeic acid. We provide a new insight into this potential drug for the treatment of myocardial I/R injury.

Diallyl trisulfide exerts cardioprotection against myocardial ischemia-reperfusion injury in diabetic state, role of AMPK-mediated AKT/GSK-3β/HIF-1α activation

“…However, when oxygen supply limits (during myocardial ischemic event), a shift in the myocardial metabolism from fatty acid to glucose is initiated as it is more oxygen efficient and prevents deleterious effects. Previously, activation of AMPK/AKT signaling has also been demonstrated to enhance myocardial glucose uptake thus alleviating MI/R injury [ 54 , 55 ]. So, the effect of diallyl trisulfide on glucose utilization during MI/R injury deserves further study.…”

Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart

“…Strong evidence indicated that AMPK/AKT pathway is involved in cardiac protection 21 , 22 . A mechanistic study showed that FGF21-induced antiapoptotic effect in T1DM mice is attributed to the activation of AMP-activated protein kinase (AMPK) followed by inactivation of phosphatase and tensin homolog (PTEN) that negatively regulates AKT signaling 12 .…”

FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice

“…Previous studies have demonstrated that AMPK, a major cellular sensor of energy availability, is involved in the progression of cardiac injury caused by different factors [32][33][34]. To explore whether AMPK is involved in FGF21 against diabetes-induced cardiac injury, we first evaluated AMPK activity in FGF21 KO and WT mice.…”