title: The cardioprotection of simvastatin in reperfused swine hearts relates to the inhibition of myocardial edema by modulating aquaporins via the PKA pathway.
abstract: OBJECTIVE
  Myocardial edema plays a role in myocardial no-reflow and infarction during ischemia and reperfusion. The effects of statins against no-reflow and infarction may relate to the inhibition of myocardial edema. The current study investigated the role of protein kinase A (PKA) in statin-reduced myocardial edema in reperfused swine hearts.
  
  
  RESULTS
  Minipigs were treated with simvastatin (SIM, 2mg/kg), SIM+H-89 (a PKA inhibitor, 1.0 μg/kg/min), or H-89 alone 1h before 90-min ischemia and 3-h reperfusion or sham operation. Ischemia or ischemia-reperfusion induced severe myocardial edema, PKA activation, and up-regulation of aquaporin-1, -4, -8, and -9 in the reflow and no-reflow myocardium. SIM pretreatment reduced the sizes of no-reflow and infarct areas by 18.5% and 11.1% (P<0.01), decreased water content in the left ventricle, reflow and no-reflow myocardium by 1.4%, 5.3%, and 4.3% (P<0.05), inhibited cardiomyocytes swelling in the reflow and no-reflow areas by 19.8% and 13.1% (P<0.01), suppressed mitochondrial water accumulation in the reflow and no-reflow areas by 49.0% and 35.9% (P<0.01), increased PKA activity (P<0.01), and blocked the up-regulation of aquaporin-1, -4, -8, and -9 in the reflow and no-reflow myocardium. However, these beneficial effects of SIM were partially abolished by inhibiting PKA with H-89.
  
  
  CONCLUSIONS
  The cardioprotective effects of acute SIM therapy against myocardial no-reflow and infarction relate to the reduction of myocardial edema by suppressing the expression of aquaporin-1, -4, -8, and -9 in a partially PKA-dependent manner.
authors: Division of Population Genetics and Prevention, State Key Laboratory of Cardiovascular Disease, FUWAI Hospital, National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
authors: Xiang-Dong
authors: XD
authors: Li
authors: Yue-Jin
authors: YJ
authors: Yang
authors: Yong-Jian
authors: YJ
authors: Geng
authors: Yu-Tong
authors: YT
authors: Cheng
authors: Hai-Tao
authors: HT
authors: Zhang
authors: Jing-Lin
authors: JL
authors: Zhao
authors: Jin-Qin
authors: JQ
authors: Yuan
authors: Run-Lin
authors: RL
authors: Gao
mesh_terms: D000818:Animals; D020346:Aquaporins / Q000037:antagonists & inhibitors* / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D004487:Edema / Q000188:drug therapy* / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D013552:Swine; D013556:Swine, Miniature
chemical_list: D020346:Aquaporins; D002316:Cardiotonic Agents; D019821:Simvastatin; D017868:Cyclic AMP-Dependent Protein Kinases