title: Pyrrolidinyl caffeamide against ischemia/reperfusion injury in cardiomyocytes through AMPK/AKT pathways.
abstract: BACKGROUND
  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 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.
  
  
  RESULTS
  Cardiomyocytes 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).
  
  
  CONCLUSIONS
  AMPK 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.
authors: Institute of Pharmacology, College of Medicine, National Taiwan University, No.1, Sec.1, Jen-Ai Road, Taipei, 100, Taiwan. leesyi5538@yahoo.com.tw.|Division of Pulmonary and Critical Care Medicine, Mackay Memorial Hospital, Taipei, Taiwan. leesyi5538@yahoo.com.tw.
authors: Shih-Yi
authors: SY
authors: Lee
authors: Institute of Pharmacology, College of Medicine, National Taiwan University, No.1, Sec.1, Jen-Ai Road, Taipei, 100, Taiwan. d97443002@ntu.edu.tw.
authors: Hui-Chun
authors: HC
authors: Ku
authors: Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan. yhkuo@ntu.edu.tw.|Department of Biotechnology, Asia University, Taichung, Taiwan. yhkuo@ntu.edu.tw.
authors: Yueh-Hsiung
authors: YH
authors: Kuo
authors: Department of Chemistry, National Taiwan University, Taipei, Taiwan. na@ntu.edu.tw.
authors: His-Lin
authors: HL
authors: Chiu
authors: Institute of Pharmacology, College of Medicine, National Taiwan University, No.1, Sec.1, Jen-Ai Road, Taipei, 100, Taiwan. mingja@ntu.edu.tw.
authors: Ming-Jai
authors: MJ
authors: Su
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002109:Caffeic Acids; D055372:AMP-Activated Protein Kinases; C040048:caffeic acid