PubMed · 4967088
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S Ito. 1967. [Recent data on thyroxine-binding protein].. https://pubmed.ncbi.nlm.nih.gov/4967088/
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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.
Stimulation of endogenous kinin receptors promotes growth of androgen-independent prostate cancer PC3 cells via activation of the mitogenic extracellular-signal-regulated kinase (ERK) pathway. In the present study, we show that kinin-mediated mitogenic signalling and prostate-cell growth involves two subtypes of bradykinin (BK) receptors, B1R and B2R. Specific stimulation of either B1R or B2R by their respective agonists des-Arg(9)-BK and Lys-BK promoted ERK activation and cell growth, whereas selective blockade with specific antagonists des-Arg(9)-[Leu(8)]BK and Hoe 140 respectively obliterated this effect, indicating the presence of both receptor subtypes. However, blockade of B1R also inhibited B2R-mediated ERK activation and cell growth, and, similarly, antagonism of B2R inhibited the B1R-mediated response. Furthermore, both B1R and B2R agonists promoted internalization of B1R, whereas both receptor antagonists blocked this effect. The B1R ligands des-Arg(9)-BK and des-Arg(9)-[Leu(8)]BK had no effect on the binding of BK to B2R, as demonstrated by radioligand competitive binding studies. However, blockade of either B1R or B2R impaired the ability of the reciprocal receptor to produce inositol phosphates, suggesting that the interaction between B1R and B2R is proximal to activation of phospholipase C. These results provide evidence for the existence of B1R-B2R complexes in prostate cancer PC3 cells and demonstrate that antagonism of one receptor interferes with the signalling ability of the other, possibly at the level of receptor-Galpha(q) protein coupling. Selective inhibition of B1R, which is up-regulated in injured and cancerous tissue, may be beneficial for the treatment of advanced prostate cancer.
BACKGROUND: A detailed understanding is evolving as to how androgen receptor (AR) functions as a transcriptional regulator via its binding to androgen response elements (ARE) within promoter and enhancer regions of prostate-specific differentiation markers such as PSA, hK2, and PSMA. It has been assumed that an understanding of regulation of expression of these marker proteins would also provide an understanding of the mechanisms whereby AR interactions regulate proliferation and survival of malignant prostate cells. In order to validate this hypothesis, we used a series of human prostate cancer models [i.e., LAPC-4, CWR22Rv1, MDA PCA-2b, LNCaP, and C4-2B (derived from LNCaP)] to test whether there is a consistent concordance between androgen responsive regulation for malignant growth vs. regulation of expression of prostate differentiation specific markers PSA, hK2, and PSMA. METHODS: In order to define androgen growth responsiveness in vivo, human prostate cancer cell lines were inoculated as xenografts into intact vs. surgically castrated adult male nude mice and the subsequent tumor growth response monitored. To assess androgen regulation of PSA and hK2 expression in these cell lines, the concentration of PSA and hK2 in the conditioned standard media and charcoal stripped media +/- androgen from each cell line was determined using an immunoassay system. PSMA enzymatic activity was determined using the PSMA substrate (3)H N-acetylaspartylglutamate ((3)H NAAG). RESULTS: Wild-type AR expressing LAPC-4 cells are androgen responsive for their in vivo growth. This cell line is also androgen sensitive for the expression of both PSA and hK2 in vitro and express PSMA. CWR22Rv1 cells have a mutated AR and are androgen responsive for growth in vivo and androgen sensitive for hk2 but not PSA expression. CWR22Rv1 produce approximately 1.4-fold more PSA, approximately 18-fold more hK2, and have 21-fold higher PSMA activity than LAPC-4 cells. MDA PCA-2b cells are androgen responsive for growth in vivo and androgen sensitive for PSA expression. MDA PCA-2b cells produce approximately 250-fold more PSA but almost equivalent amounts of hK2 compared to LAPC-4 and have approximately 19-fold higher PSMA activity. Both late passage LNCaP and C4-2B are androgen independent for growth in vivo but remain androgen sensitive for both PSA and hK2 expression. LNCaP cells produce approximately 50-fold more PSA, approximately 35-fold more hK2, and have 28-fold higher PSMA activity compared to LAPC-4. C4-2B cells produce approximately 80-fold higher levels of PSA, approximately 250-fold higher levels of hK2. C4-2B also the highest PSMA activity of the cell lines with 105-fold higher PSMA activity than LAPC-4 and approximately 4-fold higher activity than late passage LNCaP cells. CONCLUSIONS: Androgen can coordinately regulate both the tumor growth and expression of prostate specific marker genes as observed for the LAPC-4 human prostate cancer cells. Such coordinated regulation, however, is not universal. In all of the other cell lines, there is a dissociation between androgen responsive regulation of malignant growth vs. regulation of expression of prostate specific markers PSA and hK2. In addition, PSMA activity in these cell lines increases as cells become more androgen independent for growth in vivo. These results emphasize that tumor growth and the expression of the specific secretory genes are independently regulated molecular events even if they share a requirement for androgen and/or AR function. Additional independent mechanisms occur in prostate cancer cells for regulation of expression for even the highly related PSA and hK2 genes. Further studies are needed to clarify the mechanisms for androgen ligand-independent, AR-dependent regulation of the genes that directly effect the growth of androgen (i.e., ligand) independent prostate cancer cells. Unfortunately, the data in this present report do not validate the use of the PSA or hK2 gene as surrogates for a model system for such critically important mechanistic studies. Prostate prostate cancer cells. Unfortunately, the data in this present report do not validate the use of the PSA or hK2 gene as surrogates for a model system for such critically important mechanistic studies.