This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Ikeda, Y. Articles by Matsumoto, T. PubMed PubMed Citation Articles by Ikeda, Y. Articles by Matsumoto, T.

Androgen-Androgen Receptor System Protects against Angiotensin II-Induced Vascular Remodeling

Department of Medicine and Bioregulatory Sciences (Y.I., K.A., S.Yo., S.Ya., T.Iw., Y.S., T.Is., K.I., H.A., M.A., T.M.), University of Tokushima Graduate School of Health Biosciences, Tokushima 770-8503, Japan; Institute for Molecular and Cellular Regulation (T.S.), Gunma University, Maebashi 371-8512, Japan; Institute of Molecular and Cellular Biosciences (S.K.), University of Tokyo, Tokyo 113-0032, Japan; and Exploratory Research for Advanced Technology (ERATO) (S.K.), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan

Address all correspondence and requests for reprints to: Ken-ichi Aihara, M.D., Ph.D., Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. E-mail: aihara{at}clin.med.tokushima-u.ac.jp.

Age-related andropause promotes cardiovascular disease in males. Although we had previously reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and remodeling, the system’s involvement in vascular remodeling remains unclear. To clarify this role, 25-wk-old male AR knockout (ARKO) mice and littermate male wild-type (WT) mice were divided into two groups with and without angiotensin II (Ang II) administration (2.0 mg/kg · d) for 14 d, respectively. No morphological differences in the coronary artery and thoracic aorta were observed between the groups without Ang II. Ang II stimulation markedly increased medial thickness and perivascular fibrosis in ARKO mice, with enhanced TGF-β1, collagen type I, and collagen type III gene expression in the aorta. Ang II stimulation also prominently increased superoxide production, lipid peroxidation, and gene expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components in ARKO mice compared with WT mice. In addition, phosphorylation of c-Jun N-terminal kinase (JNK) and phosphorylated (Smad2/3) was remarkably enhanced in Ang II-treated ARKO mice compared with Ang II-treated WT mice. Notably, daily urinary nitric oxide (NO) metabolites excretion as a marker of NO bioavailability, aortic endothelial NO synthase expression and phosphorylation, and Akt phosphorylation were significantly reduced in ARKO mice compared with WT mice, regardless of Ang II stimulation. In conclusion, the androgen-AR system is required for the preservation of NO bioavailability through Akt-endothelial NO synthase system activation and exerts protective effects against Ang II-induced vascular remodeling by regulating oxidative stress, c-Jun N-terminal kinase (JNK) signaling, and the TGF-β-phosphorylated Smad pathway.