Impaired Arginine Metabolism Coupled to a Defective Redox Conduit Contributes to Low Plasma Nitric Oxide in Polycystic Ovary Syndrome

Abstract

Background: Though oxidative stress is associated with Polycystic Ovary Syndrome (PCOS), the status of nitric oxide is still unclear. Nitric Oxide (NO) plays pivotal roles in many physiological functions which are compromised in PCOS. Our recent study reveals lowered T-regulatory cells (Tregs) in PCOS, and Treg generation is known to be regulated by NO levels. However concrete evidences are lacking on mechanisms modulating NO levels under PCOS. Methods: This is a retrospective case-control cohort study, comprised of PCOS women (N=29) and normal menstruating women as controls (N=20). We analysed NOx (nitrite+nitrate) and hydrogen peroxide (H₂O₂) concentrations, transcript levels of endothelial nitric oxide synthase (eNOS)/inducible nitric oxide synthase (iNOS) and arginine modulators, hydrogen peroxide regulators in the cohort. Results: PCOS women showed reduced plasma NOx(nitrate+nitrite) and H₂O₂ compared to controls. We report reduction in transcript levels of iNOS/NOS2 and eNOS/NOS3 in PCOS peripheral blood. The transcripts involved in arginine bioavailability: Argininosuccinate lyase (ASL), Solute Carrier Family1, member 7 (SLC7A1) and Arginase 1 (ARG1) and Asymmetric Dimethyl Arginine (ADMA) metabolism: Protein arginine methyltransferase 1 (PRMT1) and Dimethylarginine dimethylaminohydrolase 2 (DDAH2) also showed differential expression. H₂O₂ concentration in PCOS women was also found to be reduced. The reduction can be attributed to increase in catalase levels as a consequence of the body’s effort to alleviate the oxidative burden in the system. Conclusion: Our study advocates that PCOS women have lowered NO due to reduced iNOS/eNOS expression, low H₂O₂, high ADMA synthesis and reduced arginine bioavailability. An in-depth analysis of redox biology of PCOS to open up potential therapeutic strategies is highly recommended.

Androgens drive microvascular endothelial dysfunction in women with polycystic ovary syndrome: role of the endothelin B receptor

“…; Krishna et al . ), as a result of reduced iNOS/eNOS expression concomitant with other factors of inflammation (Krishna et al . ).…”

“…), as a result of reduced iNOS/eNOS expression concomitant with other factors of inflammation (Krishna et al . ). These findings are of special interest here because earlier studies have shown similar outcomes that were independent of obesity, blood lipids and IR (Yavuz Taslipinar et al .…”

“…Androgen exposure can result in impaired agonist-triggered endothelial NO release in women, and AE-PCOS is associated with inflammation and inflammatory cytokines, oxidative stress and NF-κB activation (Diamanti-Kandarakis, 2008). The combination of high oxidative stress and poor endothelial dysfunction may lead to low levels of NO (Yavuz Taslipinar et al 2014;Krishna et al 2017), as a result of reduced iNOS/eNOS expression concomitant with other factors of inflammation (Krishna et al 2017). These findings are of special interest here because earlier studies have shown similar outcomes that were independent of obesity, blood lipids and IR (Yavuz Taslipinar et al 2014).…”

Association between VEGF gene polymorphisms (11 sites) and polycystic ovary syndrome risk

“…Pan et al demonstrated that HIF1A-mediated VEGF expression might be an important mechanism regulating ovarian luteal development in mammals in vivo, which may provide new strategies for fertility control and for treating PCOS [44]. Additional, IGF-1, TGFB1, STAT3 and NOS3 were just suggested to participate in the development of PCOS [45][46][47][48], rather than combined with VEGF. Above information predicted FLT1, KDR, and HIF1A may influence VEGF and regulate the PCOS development, which maybe become intervention and treatment target genes in the future.…”

Laboratory evaluation of vasoreactivity; asymmetric dymethylarginine, nitric oxide, fibrinogen and high sensitive C-reactive protein in patients with polycystic ovary syndrome

“…Hyperinsulinemia and IR lead to decreased release of NO and increased production of fibrinogen that both reflect atherosclerosis (14). Women with PCOS reflect blunted response to NOdependant vasodilatation which was demonstrated by many recent studies (13)(14)(15)(16)(17).…”