Inhibition of Rho kinase protects from ischaemia-reperfusion injury via regulation of arginase activity and nitric oxide synthase in type 1 diabetes.
RhoA/Rho-associated kinase and arginase are implicated in vascular complications in diabetes. This study investigated whether RhoA/Rho-associated kinase and arginase inhibition protect from myocardial ischaemia-reperfusion injury in type 1 diabetes and the mechanisms behind these effects.



Rats with streptozotocin-induced type 1 diabetes and non-diabetic rats were subjected to 30 min myocardial ischaemia and 2 h reperfusion after being randomized to treatment with (1) saline, (2) RhoA/Rho-associated kinase inhibitor hydroxyfasudil, (3) nitric oxide synthase inhibitor NG-monomethyl-l-arginine monoacetate followed by hydroxyfasudil, (4) arginase inhibitor N-omega-hydroxy-nor-l-arginine, (5) NG-monomethyl-l-arginine monoacetate followed by N-omega-hydroxy-nor-l-arginine or (6) NG-monomethyl-l-arginine monoacetate given intravenous before ischaemia.



Myocardial arginase activity, arginase 2 expression and RhoA/Rho-associated kinase activity were increased in type 1 diabetes ( p < 0.05). RhoA/Rho-associated kinase inhibition and arginase inhibition significantly reduced infarct size in diabetic and non-diabetic rats ( p < 0.001). The cardioprotective effects of hydroxyfasudil and N-omega-hydroxy-nor-l-arginine in diabetes were abolished by nitric oxide synthase inhibition. RhoA/Rho-associated kinase inhibition attenuated myocardial arginase activity in diabetic rats via a nitric oxide synthase-dependent mechanism.



Inhibition of either RhoA/Rho-associated kinase or arginase protects from ischaemia-reperfusion injury in rats with type 1 diabetes via a nitric oxide synthase-dependent pathway. These results suggest that inhibition of RhoA/Rho-associated kinase and arginase constitutes a potential therapeutic strategy to protect the diabetic heart against ischaemia-reperfusion injury.
1 Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|2 Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
Yahor
Y
Tratsiakovich
1 Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|2 Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.|3 Department of Biomedical Research, Medical University of Vienna, Vienna, Austria.
Attila
A
Kiss
1 Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|2 Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
Adrian T
AT
Gonon
1 Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|2 Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
Jiangning
J
Yang
1 Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|2 Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
Per-Ove
PO
Sjöquist
1 Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|2 Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
John
J
Pernow
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D019610:Cytoprotection; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004359:Drug Therapy, Combination; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C404735:N(omega)-hydroxynorarginine; D047428:Protein Kinase Inhibitors; C431085:hydroxyfasudil; D019323:omega-N-Methylarginine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D001120:Arginine; D019001:Nitric Oxide Synthase; D054460:rho-Associated Kinases; C113162:Arg2 protein, rat; D001119:Arginase; C000621224:RhoA protein, rat; D020741:rho GTP-Binding Proteins
Diabetes; Rho kinase; arginase; ischaemia–reperfusion