3&amp;beta;-Hydroxysteroid Dehydrogenase in Human Aorta

Nakamura, Yasuhiro; Suzuki, Takashi; Inoue, Tsukasa; Tazawa, Chika; Moriya, Takuya; Saito, Haruo; Ishibashi, Tadashi; Takahashi, Satoshi; Yamada, Satoshi; Sasano, Hironobu

doi:10.1507/endocrj.52.111

Cited by 7 publications

(4 citation statements)

References 19 publications

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“…Our data show that primary HBVSMC express the gonadal steroid receptors AR, ERα, ERβ, as well as enzymes involved in 3β-diol metabolism. This is consistent with previous studies showing that blood vessels contain AR, ERα, ERβ, and 3β-HSD [24-27,29,30]. Additionally, we found that AR and ERβ mRNA expression was not altered by cytokine treatment in our human cell model.…”

Section: Discussionsupporting

confidence: 93%

Estrogen receptor beta dependent attenuation of cytokine-induced cyclooxygenase-2 by androgens in human brain vascular smooth muscle cells and rat mesenteric arteries

2012

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Androgens may provide protective effects in the vasculature under pathophysiological conditions. Our past studies have shown that dihydrotestosterone (DHT) decreases expression of cyclooxygenase-2 (COX-2) during cytokine, endotoxin, or hypoxic stimulation in human vascular smooth muscle cells, in an androgen receptor (AR)-independent fashion. Classically DHT is regarded as a pure AR agonist; however, it can be endogenously metabolized to 5α-androstane-3β, 17β-diol (3β-diol), which has recently been shown to be a selective estrogen receptor (ERβ) agonist. Therefore, we hypothesized that DHT’s anti-inflammatory properties following cytokine stimulation are mediated through ERβ. Using primary human brain vascular smooth muscle cells (HBVSMC), we tested whether DHT’s effect on IL-1β induced COX-2 expression was mediated via AR or ERβ. The metabolism of DHT to 3β-diol is a viable pathway in HBVSMC since mRNA for enzymes necessary for the synthesis and metabolism of 3β-diol [3alpha-hydroxysteroid dehydrogenase (HSD), 3β-HSD, 17β-HSD, CYP7B1] was detected. In addition, the expression of AR, ERα, and ERβ mRNA was detected. When applied to HBVSMC, DHT (10 nM; 18 h) attenuated IL-1β-induced increases in COX-2 protein expression. The AR antagonist bicalutamide did not block DHT’s ability to reduce COX-2. Both the non-selective estrogen receptor antagonist ICI 182,780 (1 μM) and the selective ERβ antagonist PHTPP (1 μM) inhibited the effect of DHT, suggesting that DHT actions are ERβ-mediated. In HBVSMC and in rat mesenteric arteries, 3β-diol, similar to DHT, reduced cytokine-induced COX-2 levels. In conclusion, DHT appears to be protective against the progression of vascular inflammation through metabolism to 3β-diol and activation of ERβ.

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Section: Discussionsupporting

confidence: 93%

Estrogen receptor beta dependent attenuation of cytokine-induced cyclooxygenase-2 by androgens in human brain vascular smooth muscle cells and rat mesenteric arteries

2012

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“…A third and less explored pathway for androgen action is through the conversion of DHT to 3␤-diol, an ER␤ agonist (21,22,47), by the enzymes 3␤-hydroxysteroid dehydrogenase (3␤-HSD), 3␣-hydroxysteroid dehydrogenase (3␣-HSD) and 17␤-hydroxysteroid dehydrogenase (17␤-HSD) (12,19,41,44,47). Blood vessels contain AR, ER␣, ER␤, 5␣-reductase, aromatase, and 3␤-HSD (13,30,38,39); therefore, the presence of these enzymes and receptors allows for potential androgenic and estrogenic effects that can influence vascular inflammation through a variety of pathways. Our current data point to ER␤ as a possible alternative receptor pathway for the action of DHT during pathophysiological conditions.…”

Section: Discussionmentioning

confidence: 99%

Dihydrotestosterone attenuates hypoxia inducible factor-1α and cyclooxygenase-2 in cerebral arteries during hypoxia or hypoxia with glucose deprivation

Zuloaga

Gonzales

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Zuloaga KL, Gonzales RJ. Dihydrotestosterone attenuates hypoxia inducible factor-1␣ and cyclooxygenase-2 in cerebral arteries during hypoxia or hypoxia with glucose deprivation. Am J Physiol Heart Circ Physiol 301: H1882-H1890, 2011. First published August 19, 2011 doi:10.1152/ajpheart.00446.2011 attenuates cytokine-induced cyclooxygenase-2 (COX-2) in coronary vascular smooth muscle. Since hypoxia inducible factor-1␣ (HIF-1␣) activation can lead to COX-2 production, this study determined the influence of DHT on HIF-1␣ and COX-2 following hypoxia or hypoxia with glucose deprivation (HGD) in the cerebral vasculature. COX-2 and HIF-1␣ levels were assessed via Western blot, and HIF-1␣ activation was indirectly measured via a DNA binding assay. Experiments were performed using cerebral arteries isolated from castrated male rats treated in vivo with placebo or DHT (18 days) followed by hypoxic exposure ex vivo (1% O 2), cerebral arteries isolated from castrated male rats treated ex vivo with vehicle or DHT (10 or 100 nM; 18 h) and then exposed to hypoxia ex vivo (1% O 2), or primary human brain vascular smooth muscle cells treated with DHT (10 nM; 6 h) or vehicle then exposed to hypoxia or HGD. Under normoxic conditions, DHT increased COX-2 (cells 51%; arteries ex vivo 31%; arteries in vivo 161%) but had no effect on HIF-1␣. Following hypoxia or HGD, HIF-1␣ and COX-2 levels were increased; this response was blunted by DHT (cells HGD: Ϫ47% COX-2, Ϫ34% HIF-1␣; cells hypoxia: Ϫ29% COX-2, Ϫ54% HIF-1␣; arteries ex vivo: Ϫ37% COX-2; arteries in vivo: Ϫ35% COX-2) and not reversed by androgen receptor blockade. Hypoxia-induced HIF-1␣ DNA-binding was also attenuated by DHT (arteries ex vivo and in vivo: Ϫ55%). These results demonstrate that upregulation of COX-2 and HIF-1␣ in response to hypoxia is suppressed by DHT via an androgen receptor-independent mechanism. androgen; inflammation; vascular smooth muscle DESPITE THE GREATER INCIDENCE of stroke in men compared with age-matched premenopausal women (25a) and women's poorer outcomes following stroke (35), clinical studies regarding the effects of sex steroids on cerebral vascular pathophysiology remain a limited area of investigation. However, experimental research has shown that gonadal steroids modulate vascular inflammatory responses during pathological conditions (14,32,34,43). This is of great interest because the cerebral vasculature plays a central role in the pathogenesis of cardiovascular diseases, such as stroke (7), and in the initiation of inflammation after cerebral ischemia, which is a key determinant in stroke outcome (7,9). Following ischemia, inflammation is initiated by cytokine-induced activation of transcription factors such as nuclear factor-B (NF-B) and hypoxiainducible factor 1-␣ (HIF-1␣), leading to increased production of proinflammatory mediators, such as inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) (2, 46). HIF-1␣ plays a particularly important role in cerebral ischemia because it is activated both by cytokines as a result of inflamm...

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“…Immunostaining procedure and characterization of primary antibodies used in the preset study have been described previously [5][6][7].…”

Section: Immunohistochemistrymentioning

confidence: 99%

A Case of Estrogen-secreting Adrenocortical Carcinoma with Subclinical Cushing's Syndrome

et al. 2006

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Abstract.A 25-year-old man was found to have a large right adrenal mass detected by abdominal echography and computed tomography, and presented with a mild gynecomastia. Endocrine study showed increased serum concentrations and urinary excretion of estrogens and dehydroepiandorosterone sulfate (DHEA-S). The patient had no Cushingoid features but autonomous cortisol secretion, compatible with the diagnosis of subclinical Cushing's syndrome. Surgical removal of the adrenal tumor led to normalization of serum and urinary excretion of estrogens and DHEA-S. Histopathological examination revealed a high-grade adrenocortical carcinoma (ACC). The disorganized expression of all the steroidogenic enzymes in individual tumor cells was demonstrated by immunohistochemical analysis, and the abundant expression of both aromatase mRNA and insulin-like growth factor (IGF)-II mRNA was shown by RT-PCR. These data suggest the excessive secretion of estrogen as well as the ineffective steroidogenesis by the adrenal tumor. This is a very rare case of estrogen-secreting ACC associated with subclinical Cushing's syndrome.

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3β-Hydroxysteroid Dehydrogenase in Human Aorta

Cited by 7 publications

References 19 publications

Estrogen receptor beta dependent attenuation of cytokine-induced cyclooxygenase-2 by androgens in human brain vascular smooth muscle cells and rat mesenteric arteries

Estrogen receptor beta dependent attenuation of cytokine-induced cyclooxygenase-2 by androgens in human brain vascular smooth muscle cells and rat mesenteric arteries

Dihydrotestosterone attenuates hypoxia inducible factor-1α and cyclooxygenase-2 in cerebral arteries during hypoxia or hypoxia with glucose deprivation

A Case of Estrogen-secreting Adrenocortical Carcinoma with Subclinical Cushing's Syndrome

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