Ischemia‐reperfusion selectively impairs nitric oxide‐ mediated dilation in coronary arterioles: counteracting role of arginase

Abstract

A reduction in L-arginine availability has been implicated in the impairment of endothelium-dependent nitric oxide (NO)-mediated vasodilation by ischemia-reperfusion (I/R). However, the mechanisms contributing to dysregulation of the L-arginine pool remain unknown. Because endothelial cells can metabolize L-arginine via two major enzymes, that is, NO synthase (NOS) and arginase, we hypothesized that up-regulation of arginase during I/R reduces L-arginine availability to NOS and thus impairs NO-mediated vasodilation. To test this hypothesis, a local I/R was produced in the porcine heart by occlusion of a small branch of left anterior descending artery for 30 min, followed by reperfusion for 90 min. Arterioles (60-110 microm) isolated from non-ischemic and ischemic regions of subepicardium were cannulated and pressurized without flow for in vitro study. Vessels from both regions developed similar levels of basal tone. Although the dilation of I/R vessels to endothelium-independent agonist sodium nitroprusside was not altered, the endothelium-dependent NO-mediated dilations to adenosine and serotonin were attenuated. I/R not only inhibited arteriolar production of NO but also increased arteriolar arginase activity. Arginase inhibitor alpha-difluoromethylornithine enhanced NO production/dilation in normal vessels and also restored the NO-mediated function in I/R vessels. Treating I/R vessels with L-arginine also restored vasodilations. Immunohistochemical data revealed that I/R up-regulated arginase but down-regulated NOS expression in the arteriolar endothelium. Pretreating the animals with protein synthesis inhibitor cycloheximide prevented I/R-induced arginase up-regulation and also preserved NO-mediated vascular function. These results suggest that one mechanism by which I/R inhibits NO-mediated arteriolar dilation is through increased arginase activity, which limits the availability of L-arginine to NOS for NO production. In addition, the inability of arginase blockade or L-arginine supplementation to completely restore vasodilatory function may be attributable to the down-regulation of endothelial NOS expression.

Epo and Non-hematopoietic Cells: What Do We Know?

“…Epoinduced activation of NOSes in their uncoupled mode, due to the shortage of substrates and cofactors, turns these enzymes from cardioprotective anti-oxidative ones to cardiotoxic and pro-oxidative (181,183,184). Ischemia-reperfusion of coronary vessels is associated with activation of arginase-1 in the endothelium and local reduction in arginine availability (185). Oxygen deprivation inhibits eNOS and nNOS since their affinity to this substrate is rather low (186).…”

Endothelial arginase: A new target in atherosclerosis

“…Indeed, the role of arginase in endothelial dysfunction has been recently extended to other pathophysiologic conditions associated with vascular disorders in animal models such as aging [42,43], ischemia-reperfusion-induced endothelial dysfunction [44], and various types of hypertension [45,46,47 …”

Arginase II Contributes to the Ca 2+ /CaMKII/eNOS Axis by Regulating Ca 2+ Concentration Between the Cytosol and Mitochondria in a p32‐Dependent Manner

“…Arginase II, as the extrahepatic isoform, is the principal form in human and mouse aortic endothelial cells (ECs) and provides L‐ornithine for the synthesis of polyamines, putrescine, spermidine, and spermine (SPM), associated with cell proliferation and differentiation 6, 7. Arginase II is also inducible by hypoxia, lipopolysaccharide, and tumor necrosis factor‐α,8, 9, 10 and increased arginase II activity in ECs has recently been extended to other disorders in animal models, including aging,11 ischemic reperfusion,12, 13 hypertension,14, 15 balloon injury,16 and atherosclerosis 2. Although arginase II participates in the endothelial dysfunction, the mechanism through which endothelial NOS activity is regulated remains unclear.…”