title: Protein kinase A-mediated cardioprotection of Tongxinluo relates to the inhibition of myocardial inflammation, apoptosis, and edema in reperfused swine hearts.
abstract: BACKGROUND
  Our previous studies have demonstrated that Tongxinluo (TXL), a traditional Chinese medicine, can protect hearts against no-reflow and reperfusion injury in a protein kinase A (PKA)-dependent manner. The present study was to investigate whether the PKA-mediated cardioprotection of TXL against no-reflow and reperfusion injury relates to the inhibition of myocardial inflammation, edema, and apoptosis.
  
  
  METHODS
  In a 90-minute ischemia and 3-hour reperfusion model, minipigs were randomly assigned to sham, control, TXL (0.05 g/kg, gavaged one hour prior to ischemia), and TXL + H-89 (a PKA inhibitor, intravenously and continuously infused at 1.0 µg/kg per minute) groups. Myocardial no-reflow, necrosis, edema, and apoptosis were determined by pathological and histological studies. Myocardial activity of PKA and myeloperoxidase was measured by colorimetric method. The expression of PKA, phosphorylated cAMP response element-binding protein (p-CREB) (Ser(133)), tumor necrosis factor α (TNF-α), P-selectin, apoptotic proteins, and aquaporins was detected by Western blotting analysis.
  
  
  RESULTS
  TXL decreased the no-reflow area by 37.4% and reduced the infarct size by 27.0% (P < 0.05). TXL pretreatment increased the PKA activity and the expression of Ser(133) p-CREB in the reflow and no-reflow myocardium (P < 0.05). TXL inhibited the ischemia-reperfusion-induced elevation of myeloperoxidase activities and the expression of TNF-α and P-selectin, reduced myocardial edema in the left ventricle and the reflow and no-reflow areas and the expression of aquaporin-4, -8, and -9, and decreased myocytes apoptosis by regulation of apoptotic protein expression in the reflow and no-reflow myocardium. However, addition of the PKA inhibitor H-89 counteracted these beneficial effects of TXL.
  
  
  CONCLUSIONS
  PKA-mediated cardioprotection of TXL against no-reflow and reperfusion injury relates to the inhibition of myocardial inflammation, edema, and apoptosis in the reflow and no-reflow myocardium.
authors.affiliation: Department of Evidence Based Medicine, State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
authors.forename: Xiang-dong
authors.initials: XD
authors.lastname: Li
authors.forename: Yue-jin
authors.initials: YJ
authors.lastname: Yang
authors.forename: Yu-tong
authors.initials: YT
authors.lastname: Cheng
authors.forename: Ke-fei
authors.initials: KF
authors.lastname: Dou
authors.forename: Yi
authors.initials: Y
authors.lastname: Tian
authors.forename: Xian-min
authors.initials: XM
authors.lastname: Meng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051401:Aquaporin 4 / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D004487:Edema / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009205:Myocarditis / Q000517:prevention & control*; D013552:Swine; D013556:Swine, Miniature
chemical_list: D051401:Aquaporin 4; D017362:Cyclic AMP Response Element-Binding Protein; D004365:Drugs, Chinese Herbal; C513941:tongxinluo; D017868:Cyclic AMP-Dependent Protein Kinases