Abstract
BackgroundPharmacological inhibition of arginase and remote ischemic perconditioning (RIPerc) are known to protect the heart against ischemia/reperfusion (IR) injury.PurposeThe 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.MethodsAnesthetized 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.ResultsInfarct 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.ConclusionArginase 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.
Highlights
Emerging evidence suggested a pathophysiological role of arginase in several diseases related to endothelial dysfunction such as atherosclerosis [1], diabetes mellitus (DM) [2] and myocardial ischemia/reperfusion (IR) injury [3,4,5] by reducing bioavailability of nitric oxide (NO)
remote ischemic perconditioning (RIPerc) protects against IR injury via a mechanism involving inhibition of this pathway and enhanced endothelial NO synthase (eNOS) activation
There was no significant difference in mean arterial pressure (MAP) or Heart rate (HR) between the groups in protocol 1 (Table 1)
Summary
Emerging evidence suggested a pathophysiological role of arginase in several diseases related to endothelial dysfunction such as atherosclerosis [1], diabetes mellitus (DM) [2] and myocardial ischemia/reperfusion (IR) injury [3,4,5] by reducing bioavailability of nitric oxide (NO). Our group has demonstrated that inhibition of arginase either prior to ischemia or reperfusion protects the heart against IR injury through NOS- and NO-dependent mechanisms [3,4,5]. These studies confirmed that arginase activity is increased within the myocardium at risk after myocardial IR. Purpose: 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
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