PubMed · 15367447
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Bill Danby. 2004-09-14. Does testosterone affect effect?. https://doi.org/10.1503/cmaj.1040804
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Dysregulated nitric oxide (NO) signaling contributes to the pathogenesis of hypertension, a prevalent and often sex-specific risk factor for cardiovascular disease. We previously reported that mice deficient in the α1-subunit of the NO receptor soluble guanylate cyclase (sGCα1 (-/-) mice) display sex- and strain-specific hypertension: male but not female sGCα1 (-/-) mice are hypertensive on an 129S6 (S6) but not a C57BL6/J (B6) background. We aimed to uncover the genetic and molecular basis of the observed sex- and strain-specific blood pressure phenotype. Via linkage analysis, we identified a suggestive quantitative trait locus associated with elevated blood pressure in male sGCα1 (-/-)S6 mice. This locus encompasses Cyp4a12a, encoding the predominant murine synthase of the vasoconstrictor 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE). Renal expression of Cyp4a12a in mice was associated with genetic background, sex, and testosterone levels. In addition, 20-HETE levels were higher in renal preglomerular microvessels of male sGCα1 (-/-)S6 than of male sGCα1 (-/-)B6 mice. Furthermore, treating male sGCα1 (-/-)S6 mice with the 20-HETE antagonist 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) lowered blood pressure. Finally, 20-HEDE rescued the genetic background- and testosterone-dependent impairment of acetylcholine-induced relaxation in renal interlobar arteries associated with sGCα1 deficiency. Elevated Cyp4a12a expression and 20-HETE levels render mice susceptible to hypertension and vascular dysfunction in a setting of sGCα1 deficiency. Our data identify Cyp4a12a as a candidate sex-specific blood pressure-modifying gene in the context of deficient NO-sGC signaling.
BACKGROUND: Recent evidence has implicated the MAP kinase pathway with the development of androgen insensitive prostate cancer (AIPC). We have previously reported gene amplification of critical members of this pathway with the development of androgen insensitive disease. METHODS: Protein expression of Raf-1 was analyzed using immunohistochemistry (IHC) in a database of 65 paired tumor specimens obtained before and after the development of AIPC and correlated with other members of the pathway. RESULTS: Patients whose Raf-1 expression rose with development of AIPC had a significantly shorter median time to biochemical relapse compared to those whose expression fell or remained unchanged (1.16 vs. 2.62 years, P = 0.0005). In AIPC tumors, expression of Raf-1 correlated significantly with expression of HER2 and with expression of c-fos. CONCLUSIONS: We conclude that the HER2/Raf-1/AP-1 axis may promote the development of AIPC, leading to early relapse. Members of the pathway may act as novel therapeutic targets for patients.
BACKGROUND: The mechanisms underlying 1alpha,25-dihydroxyvitamin D(3) (1,25D)-induced growth inhibition of human prostate cancer cells have not been fully elucidated. To determine whether alterations in the insulin-like growth factor (IGF) signaling axis are associated with 1,25D-induced growth inhibition, we examined the ability of 1,25D to regulate expression of IGF binding proteins (IGFBPs) in human prostate cancer cell lines. METHODS: Northern and Western blot analyses were used to detect 1,25D-induced alterations in IGFBP expression. Additional in vitro studies were performed to determine the role of IGFBP-3 in 1,25D-induced growth inhibition. RESULTS: 1,25D decreased mRNA levels of the growth stimulatory IGFBP-2 and induced IGFBP-3 mRNA in LNCaP and C4-2 cells. 1,25D treatment also increased secreted IGFBP-3 protein levels in prostate cancer cell lines sensitive to 1,25D growth inhibition but had little effect on IGFBP-3 expression in 1,25D-resistant DU145 cells. However, recombinant IGFBP-3 had only a minor effect on LNCaP cell growth in the presence of serum. Furthermore, siRNA duplexes that reduced IGFBP-3 expression did not alter 1,25D growth inhibition in either LNCaP or PC-3 cell lines grown in serum-containing media. CONCLUSIONS: Our studies indicate 1,25D-induced up-regulation of IGFBP-3 is not required for the growth inhibitory effects of 1,25D in prostate cancer cells grown in serum-containing media.