PubMed · 6306450
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Y Hodgson, B Hudson. 1983. Leydig cell function.. https://doi.org/10.1007/978-3-642-81912-4_6
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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: Many of the available human prostate cancer (PC) cell lines have lost androgen sensitivity and no longer secrete prostate-specific proteins after serial culturing in cell monolayers. Three-dimensional spheroid cultures have been found to better mimic the in vivo phenotypes of several nonprostatic cell lines. METHODS: We analyzed seven PC cell lines to determine if spheroid culturing results in greater sensitivity to androgens and 1alpha,25(OH)(2) vitamin D(3) (1,25(OH)(2) D(3)) with regards to their growth, differentiation, and apoptotic potential. RESULTS: Only PC-3 cells showed greater sensitivity to the growth-inhibitory effects of 1, 25(OH)(2) D(3), while ALVA-31 showed a diminished response. The regulation of prostate-specific antigen and prostate-specific acid phosphatase remained unchanged. However, these studies provided several unique findings not observed in cell monolayers. First, three basic spheroid morphologies were observed with varying degrees of intercellular adhesions. Secondly, the cell lines that formed the tightest spheroids consistently grew at the slowest rates, regardless of their growth rate in monolayers. Lastly, 1,25(OH)(2) D(3) treatment of ALVA-31 and PPC-1 spheroids greatly reduced intercellular adhesions, and rendered ALVA-31 spheroids resistant to apoptotic induction by Fas ligand expressed via a recombinant adenoviral construct. CONCLUSIONS: Our results suggest that spheroid cultures of human PC cells may provide unique insights regarding cell adhesion and apoptotic potential that are diminished or absent in monolayer cultures.
BACKGROUND: Hox genes encode transcriptional regulatory proteins that are largely responsible for establishing the body plan of all metazoan organisms. A subset of Hox genes is expressed during the period of organogenesis and into adulthood. hoxb-13 is a recently-described member of the Hox gene family that is expressed in the spinal cord, hindgut, and urogenital sinus during embryogenesis. METHODS: Northern blot and in situ hybridization analyses of hoxb-13 expression in adult mouse tissues were performed. RESULTS: hoxb-13 mRNA is restricted to the prostate gland and distal colon in adult animals. In situ hybridization of mouse prostate tissue demonstrated that hoxb-13 is expressed in the epithelial cells of the ventral, dorsal, lateral, and anterior prostate lobes. Accumulation of hoxb-13 mRNA is not diminished following castration. CONCLUSIONS: These data demonstrate that hoxb-13 expression is androgen-independent in mouse prostate glands. The identification of hoxb-13 as an androgen-independent gene expressed in adult mouse prostate epithelial cells provides a new potential target for developing therapeutics to treat advanced prostate cancer.