兩種咖啡酸衍生物的心臟保護作用

Abstract

Background: Coronary heart disease and heart failure are the leading causes of death in the world. Developing new therapies against these diseases are still required. In myocardial ischemia/reperfusion (I/R) stress, the uncoupling of glycolysis and glucose oxidation causes lactate accumulation, cell death and myocardial infarction. In addition, the changes in cardiac oxidative stress, bioenergetics and catecholamine play major roles in the progression heart failure. Caffeic acid, one of the major phenolic constituents in nature, is as an antioxidant and known to have cardioprotective effects. In HEp3 and C2C12 cells, caffeic acid stimulates AMPK activity. Metformin, an AMPK activator, has antidiabetic and cardioprotective effects. Pyrrolidinyl caffeamide (PLCA) and caffeic acid ethanolamide (CAEA) are synthesized caffeic acid derivatives. Hence, we aimed to compare the cardioprotective effects of PLCA, CAEA with caffeic acid and metformin in this study. In the first study, we investigated the effects of PLCA on the neonatal rat ventricular myocytes (NRVM) in hypoxia/reoxygenation (H/R) stress, and its effects on the rats in myocardial I/R injury. In the second study, we explored the effects of CAEA on the pathogenesis of heart failure. Results: In the first study, cardiomyocytes were isolated and subjected to 6-hour hypoxia followed by 18-hour reoxygenation. PLCA (0.1 to 3 μM) and metformin (30 μM) were added in the different groups before hypoxia. PLCA at 1 μM and metformin at 30 μM exerted similar protective effects on NRVM in H/R stress, represented by the cell viability restoration and the cell apoptosis alleviation. PLCA up-regulated p-AMPK, p-AKT, and GLUT4 expression, and thus attenuated the accumulation of cardiac lactate and the infarct size in myocardial I/R injury. In the second study, isoproterenol increased cellular and mitochondria oxidative stress in HL-1 cells. The mice subjected to two-week isoproterenol resulted in ventricular hypertrophy, myocardial fibrosis, an elevation of lipid peroxidation, a reduction in cardiac adenosine triphosphate and left ventricular ejection fraction, suggesting oxidative stress and bioenergetics alternation in the progression of catecholamine induced cardiac dysfunction. CAEA restored oxygen consumption rates and adenosine triphosphate contents. In addition, CAEA alleviated isoproterenol induced cardiac remodeling and cardiac oxidative stress, and restored cardiac bioenergetics and function. CAEA recovered sirtuin 1 and sirtuin 3 activities, and attenuated manganese superoxide dismutase and hypoxia-inducible factor 1-α expressions, which resulted in the alleviation of isoproterenol induced cardiac injury. Conclusions: PLCA increases AMPK and AKT phosphorylation, which couples glycolysis and glucose oxidation, thereby attenuates lactate accumulation and apoptotic cell death. Therefore, we provide a potential drug to treat myocardial I/R injury in a new therapeutic strategy. In addition, CAEA prevents catecholamine induced cardiac damage, and is therefore a possible new therapeutic approach to avert heart failure progression.