title: Modification of Caffeic Acid with Pyrrolidine Enhances Antioxidant Ability by Activating AKT/HO-1 Pathway in Heart.
abstract: Overproduction of free radicals during ischemia/reperfusion (I/R) injury leads to an interest in using antioxidant therapy. Activating an endogenous antioxidant signaling pathway is more important due to the fact that the free radical scavenging behavior in vitro does not always correlate with a cytoprotection effect in vivo. Caffeic acid (CA), an antioxidant, is a major phenolic constituent in nature. Pyrrolidinyl caffeamide (PLCA), a derivative of CA, was compared with CA for their antioxidant and cytoprotective effects. Our results indicate that CA and PLCA exert the same ability to scavenge DPPH in vitro. In response to myocardial I/R stress, PLCA was shown to attenuate lipid peroxydation and troponin release more than CA. These responses were accompanied with a prominent elevation in AKT and HO-1 expression and a preservation of mnSOD expression and catalase activity. PLCA also improved cell viability and alleviated the intracellular ROS level more than CA in cardiomyocytes exposed to H2O2. When inhibiting the AKT or HO-1 pathways, PLCA lost its ability to recover mnSOD expression and catalase activity to counteract with oxidative stress, suggesting AKT/HO-1 pathway activation by PLCA plays an important role. In addition, inhibition of AKT signaling further abolished HO-1 activity, while inhibition of HO-1 signaling attenuated AKT expression, indicating cross-talk between the AKT and HO-1 pathways. These protective effects may contribute to the cardiac function improvement by PLCA. These findings provide new insight into therapeutic approaches using a modified natural compound against oxidative stress from myocardial injuries.
authors: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Hui-Chun
authors: HC
authors: Ku
authors: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Division of Pulmonary and Critical Care Medicine, Mackay Memorial Hospital, Taipei, Taiwan.|Mackay Medicine, Nursing and Management College, Taipei, Taiwan.
authors: Shih-Yi
authors: SY
authors: Lee
authors: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Kai-Chien
authors: KC
authors: Yang
authors: Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan.|Department of Biotechnology, Asia University, Taichung, Taiwan.
authors: Yueh-Hsiung
authors: YH
authors: Kuo
authors: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Ming-Jai
authors: MJ
authors: Su
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011759:Pyrrolidines / Q000737:chemistry; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016276:Ventricular Function / Q000187:drug effects
chemical_list: D000975:Antioxidants; D002109:Caffeic Acids; D002316:Cardiotonic Agents; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt; C032519:pyrrolidine; C040048:caffeic acid