Department of Structural and Functional Biology, Institute of Biology-University of Campinas (UNICAMP), Campinas, Sao Paulo, Brazil.
Life Sci. 2012 Dec 17;91(25-26):1281-7. doi: 10.1016/j.lfs.2012.09.017. Epub 2012 Oct 12.
To gain new insights into the molecular mechanisms of action of doxazosin, we investigated the prostatic stroma ultrastructure and the expression of genes involved with fibrosis, such as collagen type I and III (COL1A1 and COL3A1, respectively) and TGF-beta 1, in the rat ventral prostate.
Adult Wistar rats were treated with doxazosin (25mg/kg/day), and the ventral prostates were excised at 7 and 30days after treatment. Untreated rats were controls. Ventral prostates were subjected to ultrastructural, immunohistochemical, biochemical and molecular analyses.
Doxazosin-treated prostates showed thickened bundles of collagen fibrils, activated fibroblasts, enlarged neurotransmitter vesicles and increased tissue immunostaining for collagen type I and type III when compared to untreated prostates. After 7 and 30days of doxazosin treatment mRNA expression of COL1A1 and COL3A1 was significantly increased and reduced, respectively, compared to the control group. TGF-beta 1 mRNA and protein levels were increased after 7days of doxazosin treatment, whereas only mRNA levels remained increased after 30days of treatment.
Our data suggest that relaxation of smooth muscle cells by alpha-blockers interferes with the mechanical dynamics of the prostatic stroma extracellular matrix components, generating a pro-fibrotic effect probably via the TGF-beta 1 signaling pathway. Long term treatment with doxazosin may also lead to a reduced turnover of extracellular matrix components. Our results add to a better understanding of the molecular mechanisms behind the effects of alpha-blockade on prostatic histoarchitecture and the response to treatment for benign prostatic hyperplasia.
为了深入了解多沙唑嗪的作用机制，我们研究了大鼠前列腺基质的超微结构以及纤维化相关基因（分别为 COL1A1 和 COL3A1）和 TGF-β1 的表达。
成年 Wistar 大鼠用多沙唑嗪（25mg/kg/天）治疗，治疗后 7 天和 30 天切除前列腺腹侧叶。未治疗的大鼠为对照组。对前列腺腹侧叶进行超微结构、免疫组织化学、生化和分子分析。
与未治疗的前列腺相比，多沙唑嗪治疗的前列腺显示出胶原纤维束增厚、成纤维细胞激活、神经递质囊泡增大以及Ⅰ型和Ⅲ型胶原组织免疫染色增加。与对照组相比，多沙唑嗪治疗 7 天和 30 天后 COL1A1 和 COL3A1 的 mRNA 表达分别显著增加和减少。多沙唑嗪治疗 7 天后 TGF-β1 的 mRNA 和蛋白水平增加，而治疗 30 天后仅 mRNA 水平仍增加。
我们的数据表明，α 受体阻滞剂对平滑肌细胞的松弛作用干扰了前列腺基质细胞外基质成分的机械动力学，通过 TGF-β1 信号通路产生了促纤维化作用。长期多沙唑嗪治疗也可能导致细胞外基质成分的周转率降低。我们的结果有助于更好地理解α受体阻滞剂对前列腺组织学结构的影响以及对良性前列腺增生治疗反应的分子机制。
