title: The role of arginase and rho kinase in cardioprotection from remote ischemic perconditioning in non-diabetic and diabetic rat in vivo.
abstract: BACKGROUND
  Pharmacological inhibition of arginase and remote ischemic perconditioning (RIPerc) are known to protect the heart against ischemia/reperfusion (IR) injury.
  
  
  OBJECTIVE
  The objective of this study was to investigate whether (1) peroxynitrite-mediated RhoA/Rho associated kinase (ROCK) signaling pathway contributes to arginase upregulation following myocardial IR; (2) the inhibition of this pathway is involved as a cardioprotective mechanism of remote ischemic perconditioning and (3) the influence of diabetes on these mechanisms.
  
  
  METHODS
  Anesthetized rats were subjected to 30 min left coronary artery ligation followed by 2 h reperfusion and included in two protocols. In protocol 1 rats were randomized to 1) control IR, 2) RIPerc induced by bilateral femoral artery occlusion for 15 min during myocardial ischemia, 3) RIPerc and administration of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA), 4) administration of the ROCK inhibitor hydroxyfasudil or 5) the peroxynitrite decomposition catalyst FeTPPS. In protocol 2 non-diabetic and type 1 diabetic rats were randomosed to IR or RIPerc as described above.
  
  
  RESULTS
  Infarct size was significantly reduced in rats treated with FeTPPS, hydroxyfasudil and RIPerc compared to controls (P<0.001). FeTPPS attenuated both ROCK and arginase activity (P<0.001 vs. control). Similarly, RIPerc reduced arginase and ROCK activity, peroxynitrite formation and enhanced phospho-eNOS expression (P<0.05 vs. control). The cardioprotective effect of RIPerc was abolished by L-NMMA. The protective effect of RIPerc and its associated changes in arginase and ROCK activity were abolished in diabetes.
  
  
  CONCLUSIONS
  Arginase is activated by peroxynitrite/ROCK signaling cascade in myocardial IR. RIPerc protects against IR injury via a mechanism involving inhibition of this pathway and enhanced eNOS activation. The beneficial effect and associated molecular changes of RIPerc is abolished in type 1 diabetes.
authors.affiliation: Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Attila
authors.initials: A
authors.lastname: Kiss
authors.affiliation: Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Yahor
authors.initials: Y
authors.lastname: Tratsiakovich
authors.affiliation: Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Adrian T
authors.initials: AT
authors.lastname: Gonon
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Fedotovskaya
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johanna T
authors.initials: JT
authors.lastname: Lanner
authors.affiliation: Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Andersson
authors.affiliation: Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Jiangning
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Pernow
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019194:Ischemic Preconditioning; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; C431085:hydroxyfasudil; D030421:Peroxynitrous Acid; D019323:omega-N-Methylarginine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D001119:Arginase