Adrenal androgen dehydroepiandrosterone sulfate inhibits vascular remodeling following arterial injury

• Published in: Atherosclerosis 2009-09, Vol.206 (1), p.77-85
• Main Authors: Ii, Masaaki, Hoshiga, Masaaki, Negoro, Nobuyuki, Fukui, Ryosuke, Nakakoji, Takahiro, Kohbayashi, Eiko, Shibata, Nobuhiko, Furutama, Daisuke, Ishihara, Tadashi, Hanafusa, Toshiaki, Losordo, Douglas W, Ohsawa, Nakaaki
• Format: Article
• Language: English
• Subjects: Androgens - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular; Carotid Artery Injuries - physiopathology; Cell Cycle - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Dehydroepiandrosterone Sulfate - pharmacology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Hormones; Medical sciences; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiopathology; Rabbits; Restenosis; Tunica Intima - drug effects; Up-Regulation; Vascular smooth muscle cell
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2009.02.021

Abstract Recent epidemiologic studies have suggested that serum dehydroepiandrosterone sulfate (DHEAS) levels have a significant inverse correlation with the incidence of cardiovascular diseases. However, direct evidence for the association with DHEAS and vascular disorders has not yet been explored. DHEAS significantly reduced neointima formation 28 days after surgery without altering other serum metabolite levels in a rabbit carotid balloon injury model. Immunohistochemical analyses revealed the reduction of proliferating cell nuclear antigen (PCNA) index and increase of TdT-mediated dUTP-biotin Nick End Labeling (TUNEL) index, expressing differentiated vascular smooth muscle cell (VSMC) markers in the media 7 days after surgery. In vitro, DHEAS exhibited inhibitory effects on VSMC proliferation and migration activities, inducing G1 cell cycle arrest with upregulation of one of the cyclin dependent kinase (CDK) inhibitors p16INK4a and apoptosis with activating peroxisome proliferator-activated receptor (PPAR)-α in VSMCs. DHEAS inhibits vascular remodeling reducing neointima formation after vascular injury via its effects on VSMC phenotypic modulation, functions and apoptosis upregulating p16INK4a /activating PPARα. DHEAS may play a pathophysiological role for vascular remodeling in cardiovascular disease.