Tempol therapy attenuates medial smooth muscle cell apoptosis and neointima formation after balloon catheter injury in carotid artery of diabetic rats.
Accumulating data support the hypothesis that reactive oxygen species (ROS) play a critical role in the vascular complications observed in diabetes. However, the mechanisms of ROS-mediated vascular complications in diabetes are not clear. We tested the hypothesis that ROS-mediated increase in proapoptotic factor Bax expression leads to medial smooth muscle cell (SMC) apoptosis that is associated with neointima formation. We used a fructose-rich diet for 4 wk to model Type 2 diabetes in rats. SOD mimetic membrane-permeable 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-oxyl (Tempol, 1 mM) was administered in drinking water to scavenge superoxide starting 1 day before surgery and continued during the duration of the experiment. Vascular injury resulted in a significant increase in medial SMC apoptosis that was associated with neointima formation. The number of medial SMC positive for Bax immunostaining significantly increased in injured arteries compared with uninjured arteries. Superoxide scavenging by Tempol treatment inhibited both the Bax-positive index as well as the apoptotic index of medial SMC in response to vascular injury. Tempol treatment inhibited apoptotic loss of medial SMC, thus increasing their density in the injured arteries. These alterations in the media were associated with a marked decrease in neointima formation in injured arteries. We conclude that Bax expression may play an important role in vascular SMC apoptosis and, finally, that this regulatory mechanism is redox sensitive.
Jagadeesha
D K
DK
Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA.
Lindley
Timothy E
TE
Deleon
Jason
J
Sharma
Ram V
RV
Miller
Francis
F
Bhalla
Ramesh C
RC
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose; D002340:Carotid Artery Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D020212:Carotid Artery Injuries; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism; D005632:Fructose / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism; D017540:Tunica Media / Q000187:drug effects / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D000975:Antioxidants; C494828:Bax protein, rat; D001786:Blood Glucose; D003497:Cyclic N-Oxides; D007328:Insulin; D019253:Proto-Oncogene Proteins c-bcl-2; D013113:Spin Labels; D051028:bcl-2-Associated X Protein; D005632:Fructose; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C001803:tempol