Estradiol attenuates high glucose-induced endothelial nitrotyrosine: role for neuronal nitric oxide synthase

Abstract

Chakrabarti S, Cheung CC, Davidge ST. Estradiol attenuates high glucose-induced endothelial nitrotyrosine: role for neuronal nitric oxide synthase. Am J Physiol Cell Physiol 302: C666 -C675, 2012. First published November 30, 2011 doi:10.1152/ajpcell.00181.2011.-Hyperglycemia in diabetes causes increased oxidative stress in the vascular endothelium with generation of free radicals such as superoxide. Peroxynitrite, a highly reactive species generated from superoxide and nitric oxide (NO), induces proinflammatory tyrosine nitration of intracellular proteins under such conditions. The female sex hormone estrogen appears to exert protective effects on the nondiabetic endothelium. However, several studies show reduced vascular protection in women with diabetes, suggesting alterations in estrogen signaling under high glucose. In this study, we examined the endothelial effects of estrogen under increasing glucose levels, focusing on nitrotyrosine and peroxynitrite. Human umbilical vein endothelial cells were incubated with normal (5.5 mM) or high (15.5 or 30.5 mM) glucose before addition of estradiol (E 2, 1 or 10 nM). Selective NO synthase (NOS) inhibitors were used to determine the role of specific NOS isoforms. Addition of E2 significantly reduced high glucoseinduced increase in peroxynitrite and consequently, nitrotyrosine. The superoxide levels were unchanged, suggesting effects on NO generation. Inhibition of neuronal NOS (nNOS) reduced high glucoseinduced nitrotyrosine, demonstrating a critical role for this enzyme. E2 increased nNOS activity under normal glucose while decreasing it under high glucose as determined by its phosphorylation status. These data show that nNOS contributes to endothelial peroxynitrite and subsequent nitrotyrosine generation under high glucose, which can be attenuated by E2 through nNOS inhibition. The altered regulation of nNOS by E2 under high glucose is a potential therapeutic target in women with diabetes.

Multi-Targeted Mechanisms Underlying the Endothelial Protective Effects of the Diabetic-Safe Sweetener Erythritol

“…This higher number of death cells under HG conditions seems to be caused by an increase in NO, because addition of the NOS inhibitor L-NAME under HG conditions decreased the amount of death cells. The involvement of NO in glucose toxicity has been described previously [34], [35], [36]. Another indication of the involvement of NO in endothelial cell death was found when HUVECs were incubated with the peroxynitrite generator SIN-1.…”

Dietary Vitamin D3 Restriction Exacerbates Disease Pathophysiology in the Spinal Cord of the G93A Mouse Model of Amyotrophic Lateral Sclerosis

“…Brain cell cultures of mice exposed to 17β-estradiol significantly reduced 3-NY levels regardless of whether or not they have been exposed to superoxide [ 64 ]. Estrogen can directly inhibit nitric oxide synthase (NOS) activity, thereby reducing peroxynitrite and subsequently 3-NY generation [ 65 ].…”

The Role of Epoxyeicosatrienoic Acids in Diabetes Mellitus-Induced Impaired Vascular Relaxation of Aortic Rings in Ovariectomized Sprague-Dawley Rats

“…Premenopausal women are relatively protected against cardiovascular diseases (CVDs) compared to age-matched men, possibly because of higher circulating levels of female sex hormones (e.g., estrogen) which are believed to play a protective role by their favorable effect on vascular structure, function, and cell signaling [13–15]. However, it has been suggested that some of the estrogen effects on the endothelium may be modified or attenuated in various pathological states characterized by the increased level of oxidative stress [16, 17], which is also present in DM and has been shown to play a pivotal role in the development of diabetes complications [4–7]. It has still not been elucidated how the vasculoprotective role of estrogens is affected in women with DM who have a high incidence of CVDs.…”