α-Lipoic acid prevents neointimal hyperplasia via induction of p38 mitogen-activated protein kinase/Nur77-mediated apoptosis of vascular smooth muscle cells and accelerates postinjury reendothelialization.
OBJECTIVE
To explore whether α-lipoic acid (ALA), a naturally occurring antioxidant, inhibits neointimal hyperplasia by inducing apoptosis of vascular smooth muscle cells and to examine its potential effects on reendothelialization and platelet aggregation.


RESULTS
Restenosis and late stent thrombosis, caused by neointimal hyperplasia and delayed reendothelialization, are significant clinical problems of balloon angioplasty and drug-eluting stents. ALA treatment strongly induced apoptosis of vascular smooth muscle cells and enhanced the expression and cytoplasmic localization of Nur77, which triggers intrinsic apoptotic events. Small interfering RNA-mediated downregulation of Nur77 diminished this proapoptotic effect of ALA. Moreover, ALA increased p38 mitogen-activated protein kinase phosphorylation, and inhibition of p38 mitogen-activated protein kinase completely blocked ALA-induced vascular smooth muscle cell apoptosis and Nur77 induction and cytoplasmic localization. In balloon-injured rat carotid arteries, ALA enhanced Nur77 expression and increased TUNEL-positive apoptotic cells in the neointima, leading to inhibition of neointimal hyperplasia. This preventive effect of ALA was significantly reduced by infection of an adenovirus encoding Nur77 small hairpin (sh)RNA. Furthermore, ALA reduced basal apoptosis of human aortic endothelial cells and accelerated reendothelialization after balloon injury. ALA also suppressed arachidonic acid-induced platelet aggregation.


CONCLUSIONS
ALA could be a promising therapeutic agent to prevent restenosis and late stent thrombosis after angioplasty and drug-eluting stent implantation.
Kim
Han-Jong
HJ
Department of Internal Medicine, Kyungpook National University School of Medicine, 50 Samduk-2Ga, Jung-Gu, Daegu 700-721, Korea.
Kim
Joon-Young
JY
Lee
Sun Joo
SJ
Kim
Hye-Jin
HJ
Oh
Chang Joo
CJ
Choi
Young-Keun
YK
Lee
Hyo-Jeong
HJ
Do
Ji-Yeon
JY
Kim
Sun-Yee
SY
Kwon
Taeg-Kyu
TK
Choi
Hueng-Sik
HS
Lee
Mi-Ock
MO
Park
In-Sun
IS
Park
Keun-Gyu
KG
Lee
Ki-Up
KU
Lee
In-Kyu
IK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000187:drug effects / Q000293:injuries; D006965:Hyperplasia / Q000517:prevention & control; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D008063:Thioctic Acid / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002317:Cardiovascular Agents; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D008063:Thioctic Acid; D048051:p38 Mitogen-Activated Protein Kinases