eNOS activation and NO function: Differential control of steroidogenesis by nitric oxide and its adaptation with hypoxia

Ducsay, Charles A.; Myers, Dean A.

doi:10.1530/joe-11-0034

Cited by 48 publications

(31 citation statements)

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“…Besides cAMP signalling, NO-cGMP pathway is also involved in the regulation of Leydig cell steroidogenesis (reviewed in Ducsay & Myers, 2011). Results of this study showed that NO-cGMP signalling was more affected by Doxa-treatment independent of its duration.…”

Section: (A) (B) (D) (C)mentioning

confidence: 77%

Orally applied doxazosin disturbed testosterone homeostasis and changed the transcriptional profile of steroidogenic machinery, cAMP/cGMP signalling and adrenergic receptors in Leydig cells of adult rats

et al. 2012

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SUMMARYDoxazosin (Doxa) is an a1-selective adrenergic receptor (ADR) antagonist widely used, alone or in combination, to treat high blood pressure, benign prostatic hyperplasia symptoms, and recently has been suggested as a potential drug for prostate cancer prevention/treatment. This study was designed to evaluate the effect of in vivo Doxa po-application, in clinically relevant dose, on: (i) steroidogenic machinery homeostasis; (ii) cAMP/cGMP signalling; (iii) transcription profile of ADR in Leydig cells of adult rats. The results showed that po-application of Doxa for once (19Doxa), or for two (29Doxa) or 10 (109Doxa) consecutive days significantly disturbed steroidogenic machinery homeostasis in Leydig cells. Doxa po-application significantly decreased circulating luteinizing hormone and androgens levels. The level of androgens in testicular interstitial fluid and that extracted from testes obtained from 19Doxa/29Doxa rats decreased, although it remained unchanged in 109Doxa rats. Similarly, the ex vivo basal androgen production followed in testes isolated from 19Doxa/29Doxa rats decreased, while remained unchanged in 109Doxa rats. Differently, ex vivo testosterone production and steroidogenic capacity of Leydig cells isolated from 19Doxa/29Doxa rats was stimulated, while 109Doxa had opposite effect. In the same cells, cAMP content/release showed similar stimulatory effect, but back to control level in Leydig cells of 109Doxa. 19Doxa/29Doxa decreased transcripts for cAMP specific phosphodiesterases Pde7b/Pde8b, whereas 109Doxa increased Pde4d. All types of treatment reduced the expression of genes encoding protein kinase A (PRKA) regulatory subunit (Prkar2b), whereas only 109Doxa stimulated catalytic subunit (Prkaca). Doxa application more affected cGMP signalling: stimulated transcription of constitutive nitric oxide synthases (Nos1, Nos3) in time-dependent manner, whereas reduced inducible Nos2. 109Doxa increased guanylyl cyclase 1 transcript and PRKG1 protein in Leydig cells. Orally applied Doxa significantly disturbed the transcriptional 'signature' of steroidogenic machinery, cAMP/cGMP signalling and ADRs and b-ADRs kinases in Leydig cells, thus giving new molecular insights into the role of cAMP/cGMP/adrenalin signalling in Leydig cells homeostasis.

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Section: (A) (B) (D) (C)mentioning

confidence: 77%

Orally applied doxazosin disturbed testosterone homeostasis and changed the transcriptional profile of steroidogenic machinery, cAMP/cGMP signalling and adrenergic receptors in Leydig cells of adult rats

et al. 2012

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“…For example, the adrenal glands and ovaries of humans use LDL-derived cholesterol to produce steroid hormones (42)(43)(44). Nitric oxide inhibits steroid production ( 45 ), and the high levels of dab2 expressed in steroidogenic tissues ( 46,47 ) may facilitate LDL uptake when nitric oxide levels are low and cholesterol demand for steroid production is high. More generally, activation of ERK induces LDLR expression in dividing cells to supply the cholesterol needed for membrane biogenesis ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

S-nitrosylation of ARH is required for LDL uptake by the LDL receptor

Zhao

Pompey

Dong

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org (ARH) and the disabled-like protein 2 (dab2). Both ARH and dab2 target LDLRs to coated pits through binding sites for the LDLR, clathrin, and the adaptor protein 2 (AP-2) complex. ARH binds to the FDNPVY 807 sequence of the LDLR through a phosphotyrosine-binding (PTB) domain, to the heavy chain of clathrin through a clathrin box sequence, and to the ␤ 2-subunit of AP-2 through a sequence with strong homology to the AP-2-binding sequences of ␤ -arrestins ( 5-8 ) ( Fig. 1A ). Y807 of the FDNPVY 807 plays a critical role in the interaction of ARH and dab2 with the LDLR, and mutation of Y807 to either cysteine or alanine cripples LDLR-dependent LDL uptake ( 3,5,8,9 ). By contrast, uptake of VLDL remnants does not require ARH, dab2, or a functional FDNPVY sequence because binding of VLDL remnants to the LDLR induces a separate endocytic process that involves a second internalization motif on the LDLR cytoplasmic domain ( 10 ). It is not clear why the LDLR needs an induced process for VLDL remnant uptake when the FDNPVY-dependent process can internalize both LDL and VLDL remnants, nor why the FDNPVY process utilizes both the ARH and dab2 adaptors when either adaptor is suffi cient to support lipoprotein uptake by the LDLR.A key question is why an ARH is necessary. ARH has highest expression in kidney, liver, and placenta ( 11 ); however, dab2 is also highly expressed in both kidney and placenta, and it is dab2, not ARH, that is required for normal placental and kidney function ( 12 ). Hepatocytes and peripheral blood leukocytes lack dab2 ( 13,14 ), and ARH defi ciency in both humans and mice sharply reduces LDL clearance rates, resulting in hypercholesterolemia ( 15-18 ). Why hepatocytes and leukocytes normally rely upon ARH is unclear because both cell types lose their dependence on ARH for LDL uptake when dab2 expression is induced Abstract The LDL receptor (LDLR) relies upon endocytic adaptor proteins for internalization of lipoproteins. The results of this study show that the LDLR adaptor autosomal recessive hypercholesterolemia protein (ARH) requires nitric oxide to support LDL uptake. Nitric oxide nitrosylates ARH at C199 and C286, and these posttranslational modifi cations are necessary for association of ARH with the adaptor protein 2 (AP-2) component of clathrin-coated pits. In the absence of nitrosylation, ARH is unable to target LDL-LDLR complexes to coated pits, resulting in poor LDL uptake. The role of nitric oxide on LDLR function is specifi c for ARH because inhibition of nitric oxide synthase activity impairs ARH-supported LDL uptake but has no effect on other LDLR-dependent lipoprotein uptake processes, including VLDL remnant uptake and dab2-supported LDL uptake. These fi ndings suggest that cells that depend upon ARH for LDL uptake can control which lipoproteins are internalized by their LDLRs through changes in nitric oxide. -Zhao, Z., S. Pompey, H. Dong, J. Weng, R. Garuti, and P. Michaely. The LDL receptor (LDLR) internalizes a broad spectrum ...

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“…It is known that angiotensin II stimulates aldosterone production in H295R cells through AT1 receptor coupled to PLC, increasing the production of InsPn (Rainey et al 2004). Although HA inhibited H295R cell proliferation by increasing InsPn levels without activating aldosterone production, it is possible that HA stimulates NOS enzyme activity (via Ca 2C ), blocking steroidogenesis as described previously for MA-10 LCs by us (Mondillo et al 2009) and has been observed in other steroidogenic systems (Ducsay & Myers 2011). Regarding this, it has been demonstrated that NOS can inhibit L-type calcium channels (Wang et al 2008), which are necessary for AII-mediated steroidogenesis.…”

Section: Discussionmentioning

confidence: 62%

Histamine inhibits adrenocortical cell proliferation but does not affect steroidogenesis

Pagotto

Pereyra

Monzón

et al. 2014

Journal of Endocrinology

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Histamine (HA) is a neurotransmitter synthesized in most mammalian tissues exclusively by histidine decarboxylase enzyme. Among the plethora of actions mediated by HA, the modulatory effects on steroidogenesis and proliferation in Leydig cells (LCs) have been described recently. To determine whether the effects on LCs reported could be extrapolated to all steroidogenic systems, in this study, we assessed the effect of this amine on adrenal proliferation and steroidogenesis, using two adrenocortical cell lines as experimental models, murine Y1 cells and human NCI-H295R cells. Even when steroidogenesis was not modified by HA in adrenocortical cells, the biogenic amine inhibited the proliferation of H295R cells. This action was mediated by the activation of HRH1 subtype and an increase in the production of inositol phosphates as second messengers, causing cell-cycle arrest in the G2/M phase. These results indicate a new role for HA in the proliferation of human adrenocortical cells that could contribute to a better understanding of tumor pathology as well as to the development of new therapeutic agents.

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eNOS activation and NO function: Differential control of steroidogenesis by nitric oxide and its adaptation with hypoxia

Cited by 48 publications

References 100 publications

Orally applied doxazosin disturbed testosterone homeostasis and changed the transcriptional profile of steroidogenic machinery, cAMP/cGMP signalling and adrenergic receptors in Leydig cells of adult rats

Orally applied doxazosin disturbed testosterone homeostasis and changed the transcriptional profile of steroidogenic machinery, cAMP/cGMP signalling and adrenergic receptors in Leydig cells of adult rats

S-nitrosylation of ARH is required for LDL uptake by the LDL receptor

Histamine inhibits adrenocortical cell proliferation but does not affect steroidogenesis

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