title: Impaired perfusion after myocardial infarction is due to reperfusion-induced deltaPKC-mediated myocardial damage.
abstract: OBJECTIVE
  To improve myocardial flow during reperfusion after acute myocardial infarction and to elucidate the molecular and cellular basis that impedes it. According to the AHA/ACC recommendation, an ideal reperfusion treatment in patients with acute myocardial infarction (AMI) should not only focus on restoring flow in the occluded artery, but should aim to reduce microvascular damage to improve blood flow in the infarcted myocardium.
  
  
  METHODS
  Transgenic mouse hearts expressing the deltaPKC (protein kinase C) inhibitor, deltaV1-1, in their myocytes only were treated with or without the deltaPKC inhibitor after ischemia in an ex vivo AMI model. deltaV1-1 or vehicle was also delivered at reperfusion in an in vivo porcine model of AMI. Microvascular dysfunction was assessed by physiological and histological measurements.
  
  
  RESULTS
  deltaPKC inhibition in the endothelial cells improved myocardial perfusion in the transgenic mice. In the porcine in vivo AMI model, coronary flow reserve (CFR), which is impaired for 6 days following infarction, was improved immediately following a one-minute treatment at the end of the ischemic period with the deltaPKC-selective inhibitor, deltaV1-1 ( approximately 250 ng/kg), and was completely corrected by 24 h. Myocardial contrast echocardiography, electron microscopy studies, and TUNEL staining demonstrated deltaPKC-mediated microvascular damage. epsilonPKC-induced preconditioning, which also reduces infarct size by >60%, did not improve microvascular function.
  
  
  CONCLUSIONS
  These data suggest that deltaPKC activation in the microvasculature impairs blood flow in the infarcted tissue after restoring flow in the occluded artery and that AMI patients with no-reflow may therefore benefit from treatment with a deltaPKC inhibitor given in conjunction with removal of the coronary occlusion.
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305-5174, United States.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ikeno
authors.forename: Koichi
authors.initials: K
authors.lastname: Inagaki
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Rezaee
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
mesh_terms: D000818:Animals; D017209:Apoptosis; D003326:Coronary Circulation; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009203:Myocardial Infarction / Q000201:enzymology*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013552:Swine; D014655:Vascular Resistance
chemical_list: D009842:Oligopeptides; C477270:Ser-Phe-Asn-Ser-Tyr-Glu-Leu-Gly-Glu-Ser-Leu; D051745:Protein Kinase C-delta