Lack of direct androgen regulation of PDE5 expression

Yang, Rong; Huang, Yun‐Ching; Lin, Guiting; Wang, Guifang; Hung, Steven; Dai, Yutian; Sun, Zhen‐Gao; Lue, Tom F.; Lin, Chen

doi:10.1016/j.bbrc.2009.01.144

Cited by 24 publications

(27 citation statements)

References 33 publications

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“…The lack of a stimulatory effect of high testosterone concentrations on PDE5 expression in purified Leydig cells in vitro suggests that other systemic hormones as well as an intact microtesticular environment are required for testosterone-dependent PDE5 induction. This observation is in agreement with a recent report that PDE5 expression is not directly under androgen regulation [41] but probably depends on increased NO/cGMP production [42,43]. Furthermore, a similar expression pattern of NOS2 at two time points, 1 and 14 days of testosterone application, could be correlated with increased PDE5, PDE6D, and PDE9A expression.…”

Section: Discussionsupporting

confidence: 91%

Testosterone-Induced Modulation of Nitric Oxide-cGMP Signaling Pathway and Androgenesis in the Rat Leydig Cells1

Andrić

Janjic

Stojkov

et al. 2010

Biology of Reproduction

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Testosterone, acting as a systemic and local factor, is one of the major regulatory molecules that initiate and maintain testicular function. In the present study, different experimental approaches were used to evaluate the role of testosterone in regulation of the nitric oxide (NO)-cGMP pathway in Leydig cells derived from normal and hypogonadotropic male rats treated with testosterone for 24 h and 2 wk. Real-time quantitative PCR and Western blot analysis revealed increased inducible NO synthase (NOS2) expression followed by increased NO secretion from Leydig cells ex vivo after continuous treatment with testosterone for 2 wk in vivo. The cGMP-specific phosphodiesterases Pde5, Pde6, and Pde9 were up-regulated, whereas PRKG1 protein was decreased after a 2-wk testosterone treatment. Induction of Nos2 and Pde5 in Leydig cells was blocked by androgen receptor antagonist. In experimental hypogonadotropic hypogonadism, expression of NOS2 was significantly reduced, and treatment with testosterone increased NOS2 expression above control levels. PDE5 protein level was unchanged in hypogonadal rats, whereas treatment of hypogonadal rats with testosterone significantly increased it. In contrast, hypogonadism and testosterone replacement reduced PRKG1 protein in Leydig cells. In vitro treatment with testosterone caused gradually increased Nos2 gene expression followed by increased nitrite and cGMP production by purified Leydig cells. In summary, testosterone up-regulated NO signaling via increased NOS2 expression and contributed to down-regulation of cGMP signaling in Leydig cells. Thus, testosterone-induced modulation of NO-cGMP signaling may serve as a potent autocrine regulator of testicular steroidogenesis.

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Section: Discussionsupporting

confidence: 91%

Testosterone-Induced Modulation of Nitric Oxide-cGMP Signaling Pathway and Androgenesis in the Rat Leydig Cells1

Andrić

Janjic

Stojkov

et al. 2010

Biology of Reproduction

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“…However, recent studies have questioned this evidence, suggesting that low PDE5 in hypogonadism simply reflects the overall reduction in smooth muscle cell content 66 . Indeed, androgen deprivation triggers apoptosis of smooth muscle cells, extracellular matrix deposition 57 and accumulation of lipid droplets in mesenchymeal cells (especially in the subtunical region) contributing to impaired veno-occlusion 67 .…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Erectile dysfunction

Yafi

Jenkins

Albersen

et al. 2016

Nat Rev Dis Primers

568

500

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Erectile dysfunction is a multidimensional but common male sexual dysfunction that involves an alteration in any of the components of the erectile response, including organic, relational and psychological. Roles for nonendocrine (neurogenic, vasculogenic and iatrogenic) and endocrine pathways have been proposed. Owing to its strong association with metabolic syndrome and cardiovascular disease, cardiac assessment may be warranted in men with symptoms of erectile dysfunction. Minimally invasive interventions to relieve the symptoms of erectile dysfunction include lifestyle modifications, oral drugs, injected vasodilator agents and vacuum erection devices. Surgical therapies are reserved for the subset of patients who have contraindications to these nonsurgical interventions, those who experience adverse effects from (or are refractory to) medical therapy and those who also have penile fibrosis or penile vascular insufficiency. Erectile dysfunction can have deleterious effects on a man’s quality of life; most patients have symptoms of depression and anxiety related to sexual performance. These symptoms, in turn, affect his partner’s sexual experience and the couple’s quality of life. This Primer highlights numerous aspects of erectile dysfunction, summarizes new treatment targets and ongoing preclinical studies that evaluate new pharmacotherapies, and covers the topic of regenerative medicine, which represents the future of sexual medicine.

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“…PDE5A does not seem to be influenced by the AR (Yang, et al 2009). A handful of recent studies have provided new insight on the possible therapeutic effects of PDE5i in PCA.…”

Section: Discussionmentioning

confidence: 96%

Phosphodiesterase sequence variants may predispose to prostate cancer

Alexandre¹,

Horvath²,

Szarek³

et al. 2015

Endocrine-Related Cancer

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We hypothesized that mutations that inactivate phosphodiesterase (PDE) activity and lead to increased cyclic AMP (cAMP) and cyclic GMP (cGMP) levels may be associated with prostate cancer (PCa). We sequenced the entire PDE coding sequences in the DNA of 16 biopsy samples from PCa patients. Novel mutations were confirmed in the somatic or germline state by Sanger sequencing. Data were then compared to the 1000 Genome Project. PDE, CREB and pCREB protein expression was also studied in all samples, in both normal and abnormal tissue, by immunofluorescence. We identified 3 previously described PDE sequence variants that were significantly higher in PCa. Four novel sequence variations, one each in the PDE4B, PDE6C, PDE7B and PDE10A genes, respectively, were also found in the PCa samples. Interestingly, PDE10A and PDE4B novel variants that were present in 19% and 6% of the patients, respectively, were found in the tumor tissue only. In patients carrying PDE defects, there was pCREB accumulation (p<0.001), and an increase of the pCREB/CREB ratio (patients 0.97± 0.03; controls 0.52± 0.03; p-value < 0.001) by immunohistochemical analysis. We conclude that PDE sequence variants may play a role in the predisposition and/or progression to PCa at the germline and/or somatic state, respectively. Larger such studies are needed to confirm these findings.

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Lack of direct androgen regulation of PDE5 expression

Cited by 24 publications

References 33 publications

Testosterone-Induced Modulation of Nitric Oxide-cGMP Signaling Pathway and Androgenesis in the Rat Leydig Cells1

Testosterone-Induced Modulation of Nitric Oxide-cGMP Signaling Pathway and Androgenesis in the Rat Leydig Cells1

Erectile dysfunction

Phosphodiesterase sequence variants may predispose to prostate cancer

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