Testosterone Stimulates Duox1 Activity through GPRC6A in Skin Keratinocytes

Ko, Eunbi; Choi, Hyun Jung; Kim, Borim; Kim, Min-Sun; Park, Kkot Nara; Bae, Il-Hong; Sung, Young Kwan; Lee, Tae Ryong; Shin, Dong Wook

doi:10.1074/jbc.m114.583450

Cited by 32 publications

(24 citation statements)

References 54 publications

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“…) and ‐independent (Ko et al . ) mechanisms. This includes NADPH‐oxidase‐dependent ROS generation in ECs (Costa et al .…”

Section: Discussionmentioning

confidence: 99%

“…The simplest explanation of a possible AR-mediated NO suppressive effect is DHT induction of reactive oxygen species (ROS). Testosterone has been shown to induce ROS formation by both AR-dependent (Montezano et al 2015) and -independent (Ko et al 2014) mechanisms. This includes NADPH-oxidase-dependent ROS generation in ECs (Costa et al 2015).…”

Section: Discussionmentioning

confidence: 99%

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

Usselman

Yarovinsky

Steele

et al. 2019

The Journal of Physiology

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Key points Polycystic ovary syndrome (PCOS) is a complex syndrome with cardiovascular risk factors, including obesity and insulin resistance. PCOS is also associated with high androgens, increases the risk of cardiovascular dysfunction in women. Due to the complexity of PCOS, had it has been challenging to isolate specific causes of the cardiovascular dysfunction. Our measure of cardiovascular dysfunction (endothelial dysfunction) was most profound in lean women with PCOS. The endothelin‐1‐induced vasodilation in these PCOS subject, was dependent on the ETBR but was not NO‐dependent. We also demonstrated oestrogen administration improved endothelial function in lean and obese women with PCOS likely because oestrogen increased NO availability. Our studies indicate a primary role for androgens in cardiovascular dysfunction in PCOS. Abstract Endothelin‐1 (ET‐1) is an indicator of endothelial injury and dysfunction and is elevated in women with androgen excess polycystic ovary syndrome (AE‐PCOS). The endothelin B receptor (ETBR) subtype mediates vasodilatation, but is blunted in women with PCOS. We hypothesized that androgen drives endothelial dysfunction in AE‐PCOS women and oestradiol (EE) administration reverses these effects. We assessed microvascular endothelial function in women with (7 lean and 7 obese) and without AE‐PCOS (controls, 6 lean, 7 obese). Only obese AE‐PCOS women were insulin resistant (IR). We evaluated cutaneous vascular conductance (%CVCmax) with laser Doppler flowmetry during low dose intradermal microdialysis ET‐1 perfusions (1, 3, 4, 5 and 7 pmol) with either lactated Ringer solution alone, or with ETBR (BQ‐788), or nitric oxide (NO) inhibition (l‐NAME). Log[ET‐1]–%maxCVC dose–response curves demonstrated reduced vasodilatory responses to ET‐1 in lean AE‐PCOS (logED50, 0.59 ± 0.08) versus lean controls (logED50, 0.49 ± 0.09, P < 0.05), but not compared to obese AE‐PCOS (logED50, 0.65 ± 0.09). ETBR inhibition decreased ET‐1‐induced vasodilatation in AE‐PCOS women (logED50, 0.64 ± 0. 22, P < 0.05). This was mechanistically observed at the cellular level, with ET‐1‐induced, DAF‐FM‐measurable endothelial cell NO production, which was abrogated by dihydrotestosterone in an androgen receptor‐dependent manner. EE augmented the cutaneous vasodilating response to ET‐1(logED50 0.29 ± 0.21, 0.47 ± 0.09, P < 0.05 for lean and obese, respectively). Androgens drive endothelial dysfunction in lean and obese AE‐PCOS. We propose that the attenuated ET‐1‐induced vasodilatation in AE‐PCOS is a consequence of androgen receptor‐mediated, suppressed ETBR‐stimulated NO production, and is reversed with EE.

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“…) and ‐independent (Ko et al . ) mechanisms. This includes NADPH‐oxidase‐dependent ROS generation in ECs (Costa et al .…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Usselman

Yarovinsky

Steele

et al. 2019

The Journal of Physiology

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“…For measurement of intracellular ROS or H 2 O 2 , cells were incubated in the dark for 30 min with 5 mM 5,6-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate (Molecular Probes) or 5 mM Peroxy Orange-1 (PO-1) (Tocris Bioscience) for 15 min in phenol red-free medium, respectively [29,30]. For analysis of cell death, cells were labeled with fluorescein isothiocyanate (FITC)-Annexin V plus propidium iodide (PI) in annexin binding buffer at 25°C for 15 min, according to the manufacturer's instructions (FITC Annexin V apoptosis detection kit; BD Biosciences).…”

Section: Flow Cytometry Analysismentioning

confidence: 99%

Sulfiredoxin inhibitor induces preferential death of cancer cells through reactive oxygen species-mediated mitochondrial damage

Kim

Lee

Kim

et al. 2016

Free Radical Biology and Medicine

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“…As suggested by Barton et al (11), the orphan G protein-coupled receptor GPRC6A, which has been shown to mediate nongenomic responses to testosterone, might be a possible candidate to mediate the rapid, AR-independent effects of testosterone on ROS generation in VSMC (11). In addition, testosterone induces Duox1 activation through GPRC6A in keratinocytes that leads to H 2 O 2 generation (104).…”

Section: Other Mechanisms: Testosterone and Ros Generation/oxidative mentioning

confidence: 96%

Reactive oxygen species: players in the cardiovascular effects of testosterone

Tostes

Carneiro

Carvalho

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Tostes RC, Carneiro FS, Carvalho MH, Reckelhoff JF. Reactive oxygen species: players in the cardiovascular effects of testosterone. Am J Physiol Regul Integr Comp Physiol 310: R1-R14, 2016. First published November 4, 2015 doi:10.1152/ajpregu.00392.2014.-Androgens are essential for the development and maintenance of male reproductive tissues and sexual function and for overall health and well being. Testosterone, the predominant and most important androgen, not only affects the male reproductive system, but also influences the activity of many other organs. In the cardiovascular system, the actions of testosterone are still controversial, its effects ranging from protective to deleterious. While early studies showed that testosterone replacement therapy exerted beneficial effects on cardiovascular disease, some recent safety studies point to a positive association between endogenous and supraphysiological levels of androgens/testosterone and cardiovascular disease risk. Among the possible mechanisms involved in the actions of testosterone on the cardiovascular system, indirect actions (changes in the lipid profile, insulin sensitivity, and hemostatic mechanisms, modulation of the sympathetic nervous system and renin-angiotensin-aldosterone system), as well as direct actions (modulatory effects on proinflammatory enzymes, on the generation of reactive oxygen species, nitric oxide bioavailability, and on vasoconstrictor signaling pathways) have been reported. This mini-review focuses on evidence indicating that testosterone has prooxidative actions that may contribute to its deleterious actions in the cardiovascular system. The controversial effects of testosterone on ROS generation and oxidant status, both prooxidant and antioxidant, in the cardiovascular system and in cells and tissues of other systems are reviewed. cardiovascular; prooxidant; antioxidant TESTOSTERONE 1 IS THE PREDOMINANT and most important androgen, playing a major role in the development of male reproductive tissues (130,135). "Androgen" is a broad term for any natural or synthetic compound that primarily influences the growth and development of the male reproductive system, including the activity of the accessory male sex organs and development of male secondary sex characteristics (21, 135). Androgens are also essential for health and well being, and their beneficial and stimulant effects have been known for a long time, since the seminal studies from Brown-Séquard in the nineteenth century 2 (22, 135): "ь ь ь in the seminal fluid, as secreted by the testicles, a substance or several substances exist which, entering the blood by resorption, have a most essential use in giving strength to the nervous system and to other parts ь ь ь ."Other androgens include androstenedione, 5␣-dihydrotestosterone (DHT), which is produced from testosterone by the enzyme 5␣-reductase, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and synthetic androgens in their many steroid ester variations (e.g., testosterone cypionate, decanoate, undecanoate, enant...

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Testosterone Stimulates Duox1 Activity through GPRC6A in Skin Keratinocytes

Cited by 32 publications

References 54 publications

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

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

Sulfiredoxin inhibitor induces preferential death of cancer cells through reactive oxygen species-mediated mitochondrial damage

Reactive oxygen species: players in the cardiovascular effects of testosterone

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