Dehydroepiandrosterone Reverses Systemic Vascular Remodeling Through the Inhibition of the Akt/GSK3-β/NFAT Axis

• DOI: 10.1161/circulationaha.109.848911
• Publication Date: 2009-09-15T01:32:54Z
• Authors: Sébastien Bonnet; Roxane Paulin; Gopinath Sutendra; Peter Dromparis; Melanie Roy; Kristalee O. Watson; Jayan Nagendran; Alois Haromy; Jason R.B. Dyck; Evangelos D. Mich...
• Keywords: Male; 0301 basic medicine; Glycogen Synthase Kinase 3 beta; Cell Membrane; Cytochromes c; Apoptosis; Dehydroepiandrosterone; Muscle, Smooth, Vascular; 3. Good health; Disease Models, Animal; Glycogen Synthase Kinase 3; Kv1.5 Potassium Channel; 03 medical and health sciences; Carotid Arteries; Adjuvants, Immunologic; Hexokinase; Animals; Humans; Calcium; Carotid Artery Injuries; Angioplasty, Balloon; Cell Division; Cells, Cultured

Background— The remodeled vessel wall in many vascular diseases such as restenosis after injury is characterized by proliferative and apoptosis-resistant smooth muscle cells. There evidence that proproliferative antiapoptotic states are a metabolic (glycolytic phenotype hyperpolarized mitochondria) electric (downregulation inhibition of plasmalemmal K + channels) remodeling involves activation the Akt pathway. Dehydroepiandrosterone (DHEA) naturally occurring clinically used steroid known to inhibit axis cancer. We hypothesized DHEA will prevent reverse follows injury. Methods Results— cultured human carotid cell saphenous vein grafts tissue culture, stimulated platelet-derived growth factor induce proliferation vitro rat model vivo. decreased increased apoptosis vivo, reducing while sparing healthy tissues oral intake. Using pharmacological (agonists antagonists its downstream target glycogen-synthase-kinase-3β [GSK-3β]) molecular (forced expression constitutively active Akt1) approaches, we showed effects were mediated subsequent GSK-3β, leading mitochondrial depolarization, reactive oxygen species, redox-sensitive voltage-gated channels, [Ca 2+ ] i . These functional changes accompanied sustained toward same direction; decreasing inhibiting inhibited nuclear activated T cells transcription factor, thus increasing Kv channels (Kv1.5) contributing depolarization. results independent any steroid-related because they not altered androgen estrogen inhibitors but involved membrane G protein–coupled receptor. Conclusions— suggest orally available might be an attractive candidate for treatment systemic remodeling, including restenosis, propose novel mechanism action this important hormone drug.