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

Shih-Yi Lee,Ming-Jai Su,His-Lin Chiu,Hui-Chun Ku,Yueh-Hsiung Kuo

doi:10.1186/s12929-015-0125-3

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.

Highlights

Coronary heart disease is a leading cause of death in the world and therapy to reduce injury is still needed
Comparison of the protective effects of Pyrrolidinyl caffeamide (PLCA) and metformin in neonatal rat ventricular myocytes (NRVM) after H/R stress To determine whether PLCA exerted a protective effect during the H/R condition, cell viability was assessed via MTT assay
Comparison of the protein expression between PLCA and metformin in NRVM after H/R stress To investigate the mechanisms of the protective effects of PLCA and metformin in NRVM during in the H/R condition, we evaluated the expression of several proteins

Summary

Introduction

Coronary 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 leads to myocardial infarction. Pyrrolidinyl caffeamide (PLCA), a new derivative of caffeic acid, was synthesized by our team. Coronary heart disease is a leading cause of death in the world [1]. With ischemia in coronary heart disease, impairment of the oxygen supply and metabolic disorder both occur [2]. Anaerobic glycolysis occurs accompanied by lactate accumulation, leading to intracellular acidosis [2]. A high intracellular calcium concentration and the production excess reactive oxygen species inhibit the mitochondrial electron transport chain causing cell damage [5].

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