Oxidized Low-Density Lipoprotein–Dependent Endothelial Arginase II Activation Contributes to Impaired Nitric Oxide Signaling

Abstract

Abstract-Oxidized low-density lipoprotein (OxLDL) impairs NO signaling and endothelial function, and contributes to the pathogenesis of atherosclerosis. Arginase reciprocally regulates NO levels in endothelial cells by competing with NO synthase for the substrate L-arginine. In human aortic endothelial cells, OxLDL stimulation increased arginase enzyme activity in a time-and dose-dependent manner. Arginase activity reached its maximum as early as 5 minutes, was maintained for a period of more than 48 hours, and was associated with a reciprocal decrease in NO metabolite (NOx [nitrite and nitrate]) production. Furthermore, OxLDL induced arginase II mRNA expression after 4 hours. Small interfering RNA targeted to arginase II decreased both the quantity and the activity of arginase from baseline, prevented OxLDL-dependent increases in arginase activity, and induced an increase in NOx production. Immunofluorescence analysis revealed an association of arginase II with the microtubule cytoskeleton. Microtubule disruption with nocodazole caused a dramatic redistribution of arginase II to a diffuse cytosolic pattern, increased arginase activity, and decreased NOx production, which was restored in the presence of the specific arginase inhibitor (S)-(2-boronoethyl)-L-cysteine (BEC). On the other hand, epothilone B prevented microtubule disruption and inhibited OxLDL-dependent increases in arginase activity and attenuated OxLDL-dependent decreases in NOx. Preincubation of rat aortic rings with OxLDL resulted in an increase in arginase activity and a decrease in NOx production. This was reversed by arginase inhibition with the BEC. Thus, OxLDLs increase arginase activity by a sequence of regulatory events that involve early activation through decreased association with microtubules and a later increase in transcription. Furthermore, increased arginase activity contributes to OxLDL-dependent impairment of NOx production. Arginase, therefore, represents a novel target for therapy in atherosclerosis.

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

“…Arginase is reported to reciprocally regulate NOS [29] by modulating L-arginine bioavailability. Arginase upregulation is reported to contribute to impaired NO signaling as a result of aging [45] as well as following treatment of ECs to Ox-LDL [29] and is suggested to be a therapeutic target. However, arginase inhibition failed to affect CRP-mediated eNOS inhibition, excluding arginase upregulation in the present study.…”

Arginase Inhibition by Ethylacetate Extract ofCaesalpinia sappanLignum Contributes to Activation of Endothelial Nitric Oxide Synthase

“…The activation and expression of endothelial arginase II can also be induced by a variety of vascular stimulants, including OxLDL, LPS, TNF-α, IFN-γ, 8-bromocGMP, and hypoxia [7,10,[12][13][14]. Arginase activation/upregulation results in arginase/NOS imbalance, as well as de-creased NO production, and has been demonstrated to contribute to endothelial dysfunction, in a number of diseases/ pathophysiological processes, including aging [4], diabetes [15][16][17], hypertension [18][19][20], and atherosclerosis [14,21].…”

Ghrelin, Nitrite and Paraoxonase/Arylesterase Concentrations in Cement Plant Workers

“…Also, it has been reported that LDL, especially ox-LDL, is a potent inhibitor of endothelial function (19,20). The mechanisms by which LDL inhibits endothelial-derived NO activity include the down-regulation of endothelial NO expression (20,21), decreased receptor-mediated NO release (20), and NO inactivation via increases in O 2 − production (22,23). Indeed, endo thelial dysfunction is a hallmark of hypercholesterolemia and is rapidly improved by cholesterol reduction (24).…”