title: Inhibition of contractile activity during postconditioning enhances cardioprotection by restoring sarcolemmal dystrophin through phosphatidylinositol 3-kinase.
abstract: BACKGROUND
  Although ischemic postconditioning (IPost) confers cardioprotection by protecting the mitochondria though the activation of phosphatidylinositol 3-kinase (PI3K), a potential drawback of IPost is impairment of aerobic ATP generation during reperfusion by repeated ischemia. This decrease in ATP might inhibit the restoration of sarcolemmal dystrophin, which is translocated during ischemia, and render cardiomyocytes susceptible to contraction-induced oncosis.
  
  
  RESULTS
  Isolated rat hearts were subjected to 30 min ischemia and 120 min reperfusion. IPost induced by 20 cycles of 10-s reperfusion and 10-s ischemia enhanced the activation of PI3K as evidenced by the increased phosphorylation of Akt, but had no effect on myocardial ATP, restoration of sarcolemmal dystrophin, or cardiomyocyte oncosis during IPost. Administration of the contractile blocker, 2,3-butanedione monoxim (BDM), during IPost increased myocardial ATP and facilitated the redistribution of dystrophin to the sarcolemma. This led to reduced cardiomyocyte oncosis and infarct size, and improved the left ventricular function. The anti-oncotic effect of BDM occurred without changing the anti-apoptotic effect of IPost. The PI3K inhibitor, LY294002, prevented the phosphorylation of Akt, decreased the recovery of ATP and restoration of sarcolemmal dystrophin, and blocked the anti-oncotic and anti-apoptotic effects of IPost.
  
  
  CONCLUSIONS
  These results suggest that the inhibition of contractile activity during IPost prevents cardiomyocyte oncosis and enhances cardioprotection through PI3K-dependent restoration of sarcolemmal dystrophin.
authors.affiliation: The Second Department of Internal Medicine, Kansai Medical University, Moriguchi, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Moriguchi
authors.forename: Hajime
authors.initials: H
authors.lastname: Otani
authors.forename: Kei
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shimazu
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujita
authors.forename: Toru
authors.initials: T
authors.lastname: Okazaki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sato
authors.forename: Shiori
authors.initials: S
authors.lastname: Kyoi
authors.forename: Toshiji
authors.initials: T
authors.lastname: Iwasaka
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D019610:Cytoprotection; D003931:Diacetyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D016189:Dystrophin / Q000378:metabolism*; D004789:Enzyme Activation; D066298:In Vitro Techniques; D057775:Ischemic Postconditioning; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010477:Perfusion; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000255:Adenosine Triphosphate; D002867:Chromones; D003931:Diacetyl; D016189:Dystrophin; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C004717:diacetylmonoxime; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one