title: PTOV1: a novel testosterone-induced atherogenic gene in human aorta.
abstract: There are gender differences in the development of atherosclerosis, possibly owing to differences in sex steroid hormone action and/or metabolism. One of the atherogenic effects of testosterone is thought to be androgen receptor (AR)-mediated vascular smooth muscle cell (VSMC) proliferation. However, the detailed mechanism of this effect, particularly the identity of the genes associated with VSMC proliferation, remains largely unknown. Therefore, we first employed microarray analysis and, subsequently, quantitative RT-PCR to analyse RNA expression in AR-positive human VSMCs treated with testosterone in order to detect testosterone-induced genes associated with cell proliferation. We further examined whether the genes identified were involved in cell proliferation using small interfering RNA (siRNA) transfection. Expression of the gene products was then evaluated in human aorta with various degrees of atherosclerosis in order to evaluate the clinical relevance of the findings. Both microarray and quantitative RT-PCR analyses demonstrated marked induction of the human prostate overexpressed protein 1 (PTOV1) gene by testosterone in the cell lines: this gene was recently identified as a novel androgen-induced gene involved in prostate tumour cell proliferation. Inhibition of PTOV1 by transfection of its corresponding siRNA suppressed testosterone-induced cell proliferation. In human aorta, PTOV1 immunoreactivity in the nuclei of neointimal VSMCs was abundantly detected in male aorta with mild atherosclerotic changes compared with female aorta or male aorta with severe atherosclerotic changes. These findings indicate that the PTOV1 gene is androgen-responsive in VSMCs and that it may play an important role in androgen-related atherogenesis in the human aorta, particularly early atherosclerosis in the male aorta, through regulating proliferation of neointimal VSMCs.
authors.affiliation: Department of Pathology, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Igarashi
authors.forename: J
authors.initials: J
authors.lastname: Kanno
authors.forename: T
authors.initials: T
authors.lastname: Furukawa
authors.forename: C
authors.initials: C
authors.lastname: Tazawa
authors.forename: F
authors.initials: F
authors.lastname: Fujishima
authors.forename: I
authors.initials: I
authors.lastname: Miura
authors.forename: T
authors.initials: T
authors.lastname: Ando
authors.forename: N
authors.initials: N
authors.lastname: Moriyama
authors.forename: T
authors.initials: T
authors.lastname: Moriya
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: H
authors.initials: H
authors.lastname: Sasano
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D001012:Aorta, Abdominal; D050197:Atherosclerosis / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016009:Chi-Square Distribution; D005485:Flutamide / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000378:metabolism*; D017539:Tunica Intima; D048868:Adaptor Proteins, Signal Transducing
chemical_list: D000726:Androgen Antagonists; D014408:Biomarkers, Tumor; D005485:Flutamide; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D013739:Testosterone; C425183:PTOV1 protein, human; D048868:Adaptor Proteins, Signal Transducing