PubMed · 1735475
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H D McClamrock, E Y Adashi. 1992. Gestational hyperandrogenism.. https://doi.org/10.1016/s0015-0282(16)54828-6
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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: There is no effective therapy currently available for androgen-independent (AI) prostate cancer (CaP). This is largely due to lack of information about the molecular mechanisms by which androgen-dependent tumor cells progress to androgen independence. In this study, we investigated molecular alterations occurring in AI LNCaP cells. METHODS: We established and characterized three AI LNCaP sublines that exhibited a wide range of cytogenetic alterations. In order to understand why androgen-sensitive LNCaP cells can survive in an androgen-deprived environment, we analyzed the expression of signaling proteins associated with proliferation and survival of AI cells. In addition, gene expression profiling was performed to gain insight into molecular alterations in these LNCaP sublines. RESULTS: These LNCaP sublines exhibited heightened levels of androgen receptor (AR), HER2, MAPK, serine 473-phosphorylated Akt, and Bcl-2, implicating these proteins as mediators of AI growth. Gene expression profiling identified a common set of 66 genes that were differentially expressed in all three sublines compared to the parental LNCaP cells. Of these, 32 were apparently androgen regulated, while the remainder comprised an expression signature specific for androgen independence. CONCLUSION: We have developed AI LNCaP cell models and identified several genes that are specifically expressed in these models. Elucidating the relative importance of these genetic changes will help define the molecular mechanism by which CaP progresses to androgen independence.
Lethal phenotypes of human prostate cancer are characterized by progression to androgen-independence and metastasis. For want of a clinically relevant animal model, mechanisms behind this progression remain unclear. Our study used an in vivo model of androgen-sensitive LNCaP human prostate cancer cell xenografts in male SCID mice to study the cellular and molecular biology of tumor progression. Primary tumors were established orthotopically, and the mice were then surgically castrated to withdraw androgens. Five generations of androgen-independent tumors were developed using castrated host mice. Tumor samples were used to determine expressions of cellular and molecular markers. Androgen-independent tumors had increased proliferation and decreased apoptosis compared to androgen-sensitive tumors, outcomes associated with elevated expression of p53, p21/waf1, bcl-2, bax and the bcl-2/bax ratio. Blood vessel growth in androgen-independent tumor was associated with increased expression of vascular endothelial growth factor. Overexpression of androgen receptor mRNA and reduced expression of androgen receptor protein in androgen-independent tumors suggest that the androgen receptor signaling pathway may play an important role in the progression of human prostate cancer to androgen-independence. The in vivo orthotopic LNCaP tumor model described in our study mimics the clinical course of human prostate cancer progression. As such, it can be used as a model for defining the molecular mechanisms of prostate cancer progression to androgen-independence and for evaluating the effect of preventive or therapeutic regimens for androgen-independent human prostate cancer.