Adrenal androgen dehydroepiandrosterone sulfate inhibits vascular remodeling following arterial injury.
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 p16(INK4a) and apoptosis with activating peroxisome proliferator-activated receptor (PPAR)-alpha in VSMCs. DHEAS inhibits vascular remodeling reducing neointima formation after vascular injury via its effects on VSMC phenotypic modulation, functions and apoptosis upregulating p16(INK4a)/activating PPARalpha. DHEAS may play a pathophysiological role for vascular remodeling in cardiovascular disease.
Ii
Masaaki
M
The First Department of Internal Medicine, Osaka Medical College, Osaka, Japan. masa0331@mac.com
Hoshiga
Masaaki
M
Negoro
Nobuyuki
N
Fukui
Ryosuke
R
Nakakoji
Takahiro
T
Kohbayashi
Eiko
E
Shibata
Nobuhiko
N
Furutama
Daisuke
D
Ishihara
Tadashi
T
Hanafusa
Toshiaki
T
Losordo
Douglas W
DW
Ohsawa
Nakaaki
N
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020212:Carotid Artery Injuries / Q000503:physiopathology*; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology; D011817:Rabbits; D017539:Tunica Intima / Q000187:drug effects; D015854:Up-Regulation
D000728:Androgens; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019314:Dehydroepiandrosterone Sulfate