Dehydroepiandrosterone reverses systemic vascular remodeling through the inhibition of the Akt/GSK3-{beta}/NFAT axis.
BACKGROUND
The remodeled vessel wall in many vascular diseases such as restenosis after injury is characterized by proliferative and apoptosis-resistant vascular smooth muscle cells. There is evidence that proproliferative and antiapoptotic states are characterized by a metabolic (glycolytic phenotype and hyperpolarized mitochondria) and electric (downregulation and inhibition of plasmalemmal K(+) channels) remodeling that involves activation of the Akt pathway. Dehydroepiandrosterone (DHEA) is a naturally occurring and clinically used steroid known to inhibit the Akt axis in cancer. We hypothesized that DHEA will prevent and reverse the remodeling that follows vascular injury.


RESULTS
We used cultured human carotid vascular smooth muscle cell and saphenous vein grafts in tissue culture, stimulated by platelet-derived growth factor to induce proliferation in vitro and the rat carotid injury model in vivo. DHEA decreased proliferation and increased vascular smooth muscle cell apoptosis in vitro and in vivo, reducing vascular remodeling while sparing healthy tissues after oral intake. Using pharmacological (agonists and antagonists of Akt and its downstream target glycogen-synthase-kinase-3beta [GSK-3beta]) and molecular (forced expression of constitutively active Akt1) approaches, we showed that the effects of DHEA were mediated by inhibition of Akt and subsequent activation of GSK-3beta, leading to mitochondrial depolarization, increased reactive oxygen species, activation of redox-sensitive plasmalemmal voltage-gated K(+) channels, and decreased [Ca(2+)](i). These functional changes were accompanied by sustained molecular effects toward the same direction; by decreasing [Ca(2+)](i) and inhibiting GSK-3beta, DHEA inhibited the nuclear factor of activated T cells transcription factor, thus increasing expression of Kv channels (Kv1.5) and contributing to sustained mitochondrial depolarization. These results were independent of any steroid-related effects because they were not altered by androgen and estrogen inhibitors but involved a membrane G protein-coupled receptor.


CONCLUSIONS
We suggest that the orally available DHEA might be an attractive candidate for the treatment of systemic vascular remodeling, including restenosis, and we propose a novel mechanism of action for this important hormone and drug.
Bonnet
Sébastien
S
Centre de Recherche de L'Hôtel-Dieu de Québec, 9 Rue McMahon, Québec, Qc, G1R 2J6, Canada. sebastien.bonnet@crhdq.ulaval.ca
Paulin
Roxane
R
Sutendra
Gopinath
G
Dromparis
Peter
P
Roy
Melanie
M
Watson
Kristalee O
KO
Nagendran
Jayan
J
Haromy
Alois
A
Dyck
Jason R B
JR
Michelakis
Evangelos D
ED
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002339:Carotid Arteries / Q000166:cytology; D020212:Carotid Artery Injuries / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D016491:Peripheral Vascular Diseases / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
D000276:Adjuvants, Immunologic; C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; D050778:NFATC Transcription Factors; C494762:VDAC1 protein, human; C494764:Vdac1 protein, rat; D003687:Dehydroepiandrosterone; D045304:Cytochromes c; D050995:Voltage-Dependent Anion Channel 1; D006593:Hexokinase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D002118:Calcium