P419Involvement of arginase and Rho kinase in the cardioprotecive effect of remote ischemic perconditioning in vivo

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Aims: It is well established that remote ischemic perconditioning (RIPerc) effectively protects from myocardial ischemia-reperfusion (IR) injury. The signaling events underlying the cardioprotective effect seem to involve nitric oxide (NO) but the exact mechanism remains unclear. We have recently demonstrated that IR injury is critically dependent on increased arginase activity resulting in reduced bioavailability of NO. The objective of this study was to investigate whether (1) oxidative/nitrosative stress-mediated RhoA/Rho kinase (ROCK) signaling pathway contributes to arginase upregulation following IR and (2) the inhibition of this pathway is involved as a cardioprotective mechanism of RIPerc.

Methods: Anesthetized Sprague-Dawley rats subjected to 30 min left coronary artery ligation and 2 h reperfusion were randomized to: 1) no intervention (controls, n=10), 2) RIPerc induced by bilateral femoral artery occlusion during the last 15 min of myocardial ischemia (n=10), 3) RIPerc and administration of the NO synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA; n=6), 4) administration of the ROCK inhibitor hydroxyfasudil (20 min prior to ischemia iv; n=7), or 5) administration of the peroxynitrite decomposition catalyst FeTPPS (10 min prior to reperfusion iv; n=6).

Results: Infarct size (as a percentage of the area at risk) was significantly smaller in animals subjected to RIPerc (42±4%) compared to the controls (69±2%; P<0.001). The cardioprotective effect of RIPerc was abolished by the administration of L-NMMA. Administration of hydroxyfasudil (49±3%) or FeTPPS (51±4%) also reduced infarct size (P<0.01). Furthermore, RIPerc markedly attenuated arginase activity, ROCK activity, generation of peroxynitrite and enhanced phosphorylated eNOS (ser1177) expression (P<0.05 vs. control). Similarly, rats treated with FeTPPS attenuated both ROCK and arginase activity (P<0.05 vs. control).

Conclusion: These findings suggest that arginase is affected by peroxynitrite/ROCK signaling cascade in the setting of myocardial IR. RIPerc protects from IR injury via mechanism that involves inhibition of this pathway resulting in enhanced NOS activity.

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