Fibrosis-related gene expression in the prostate is modulated by doxazosin treatment.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Structural and Functional Biology, Institute of Biology-University of Campinas (UNICAMP), Campinas, Sao Paulo, Brazil.
Flávia K
FK
Delella
Livia M
LM
Lacorte
Fernanda Losi A
FL
Almeida
Maeli Dal
MD
Pai
Sérgio L
SL
Felisbino
D058668:Adrenergic alpha-1 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D024043:Collagen Type II / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D017292:Doxazosin / Q000008:administration & dosage / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011467:Prostate / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D058668:Adrenergic alpha-1 Receptor Antagonists; C577828:COL3A1 protein, rat; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024043:Collagen Type II; D024061:Collagen Type III; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D017292:Doxazosin