Effect of arginase inhibition on ischemia-reperfusion injury in patients with coronary artery disease with and without diabetes mellitus

Oskar Kövamees, Alexey Shemyakin, John Pernow, Oskar Kövamees, Alexey Shemyakin, John Pernow

Abstract

Background: Arginase competes with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in coronary artery disease (CAD) and diabetes mellitus may reduce nitric oxide bioavailability contributing to endothelial dysfunction and ischemia-reperfusion injury. Arginase inhibition reduces infarct size in animal models. Therefore the aim of the current study was to investigate if arginase inhibition protects from endothelial dysfunction induced by ischemia-reperfusion in patients with CAD with or without type 2 diabetes (

Clinical trial registration number: NCT02009527).

Methods: Male patients with CAD (n = 12) or CAD + type 2 diabetes (n = 12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and after 20 min ischemia-reperfusion during intra-arterial infusion of the arginase inhibitor (Nω-hydroxy-nor-L-arginine, 0.1 mg/min) or saline.

Results: The forearm ischemia-reperfusion was well tolerated. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Ischemia-reperfusion decreased FMD in patients with CAD from 12.7±5.2% to 7.9±4.0% during saline administration (P<0.05). Nω-hydroxy-nor-L-arginine administration prevented the decrease in FMD in the CAD group (10.3±4.3% at baseline vs. 11.5±3.6% at reperfusion). Ischemia-reperfusion did not significantly reduce FMD in patients with CAD + type 2 diabetes. However, FMD at reperfusion was higher following nor-NOHA than following saline administration in both groups (P<0.01). Endothelium-independent vasodilatation did not differ between the occasions.

Conclusions: Inhibition of arginase protects against endothelial dysfunction caused by ischemia-reperfusion in patients with CAD. Arginase inhibition may thereby be a promising therapeutic strategy in the treatment of ischemia-reperfusion injury.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Study protocol.
Figure 1. Study protocol.
FMD, flow-mediated dilatation; NaCl, sodium chloride; Nor-NOHA, Nω-hydroxy-nor-arginine; NTG, nitroglycerine.
Figure 2. Flow-mediated dilatation of the radial…
Figure 2. Flow-mediated dilatation of the radial artery for patients with CAD and CAD+DM respectively.
Flow-mediated dilatation (FMD) of the radial artery at baseline and after ischemia-reperfusion (I-R) in patients with coronary artery disease (CAD) and CAD plus type 2 diabetes mellitus (CAD+DM) following administration of saline or the arginase inhibitor Nω-hydroxy-nor-arginine (nor-NOHA). Data are presented as means and SD; *P<0.05, **P<0.01.
Figure 3. Response to ischemia-reperfusion.
Figure 3. Response to ischemia-reperfusion.
Change in flow-mediated dilatation (FMD) from baseline induced by ischemia-reperfusion in patients with coronary artery disease (CAD) and CAD plus type 2 diabetes mellitus (CAD+DM) given saline or the arginase inhibitor Nω-hydroxy-nor-arginine (nor-NOHA). Data are presented as means and SD; *P<0.05, ***P<0.001.

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