Abstract
BackgroundElevated arginase (Arg) activity is reported to be involved in diabetes-induced vascular endothelial dysfunction. It can reduce L-arginine availability to nitric oxide (NO) synthase (NOS) and NO production. Akita mice, a genetic non-obese type 1 diabetes model, recapitulate human diabetes. We determined the role of Arg in a time-course of diabetes-associated endothelial dysfunction in aorta and corpora cavernosa (CC) from Akita mice.Methods and ResultsEndothelium-dependent relaxation, Arg and NOS activity, and protein expression levels of Arg and constitutive NOS were assessed in aortas and CC from Akita and non-diabetic wild type (WT) mice at 4, 12 and 24 wks of age. Systolic blood pressure (SBP) was assessed by tail cuff. In aorta and CC, Akita mice exhibited a progressive impairment of vascular endothelial and nitrergic function increased Arg activity and expression (Arg1 in aorta and both Arg1 and Arg2 in CC) compared with that of age-matched WT mice. Treatment of aorta and CC from Akita mice with an Arg inhibitor (BEC or ABH) reduced diabetes-induced elevation of Arg activity and restored endothelial and nitrergic function. Reduced levels of phospho-eNOS at Ser1177 (in aorta and CC) and nNOS expression (in CC) were observed in Akita mice at 12 and 24 wks. Akita mice also had decreased NOS activity in aorta and CC at 12 and 24 wks that was restored by BEC treatment. Further, Akita mice exhibited moderately increased SBP at 24 wks and increased sensitivity to PE-induced contractions in aorta and sympathetic nerve stimulation in CC at 12 and 24 wks.ConclusionsOver 24 wks of diabetes in Akita mice, both aortic and cavernosal tissues exhibited increased Arg activity/expression, contributing to impaired endothelial and nitrergic function and reduced NO production. Our findings demonstrate involvement of Arg activity in diabetes-induced impairment of vascular function in Akita mouse.
Highlights
Vascular endothelial dysfunction is associated with many vascular disorders including diabetes and is accepted as a major cause of morbidity and mortality in diabetic patients
Our findings demonstrate involvement of Arg activity in diabetes-induced impairment of vascular function in Akita mouse
Profile of Akita Mice polymerase chain reaction (PCR) analysis confirmed that the mutant gene of Akita mouse was observed at 280 bp, while the wild type (WT) gene is seen at 140 bp (Figure 1A)
Summary
Vascular endothelial dysfunction is associated with many vascular disorders including diabetes and is accepted as a major cause of morbidity and mortality in diabetic patients. Recent evidence indicates that elevated arginase activity contributes to impaired nitrergic and endothelium-mediated relaxation of smooth muscle in diabetes and hypertension [7,8]. Given that NO synthase (NOS) and arginase share L-arginine as their common substrate, elevation of arginase activity can limit availability of L-arginine for NOS, thereby reducing NO production and impairing vascular function. Inhibition of arginase has been shown to enhance NO production [1] and reduce endothelial dysfunction in hypertensive, high fat diet and diabetic states [7,13,14], while overexpression of arginase decreases intracellular L-arginine levels and suppresses NO synthesis [15,16]. Elevated arginase (Arg) activity is reported to be involved in diabetes-induced vascular endothelial dysfunction. It can reduce L-arginine availability to nitric oxide (NO) synthase (NOS) and NO production. We determined the role of Arg in a time-course of diabetes-associated endothelial dysfunction in aorta and corpora cavernosa (CC) from Akita mice
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