Regulation of vascular smooth muscle cell growth by aldose reductase.
Aldose reductase (AR) is a broad-specificity aldo-keto reductase with wide species and tissue distribution. The enzyme has been implicated in the development of pleiotropic complications of long-term diabetes. However, the euglycemic function of the enzyme remains unclear. To examine its potential role in cell growth, changes in AR mRNA and protein were measured in human aortic smooth muscle cells exposed in culture to serum or thrombin. Stimulation by these mitogens led to an increase in the abundance of AR mRNA and protein. Furthermore, inhibition of the AR by tolrestat and sorbinil diminished DNA synthesis and cell proliferation in response to serum. Immunohistochemical staining with anti-AR antibodies revealed no significant expression of AR in the smooth muscle cells of rat carotid arteries. However, 10 and 21 days after balloon injury, intense staining was associated with the proliferating cells of the neointima. Treatment of these animals with 40 mg/kg/day sorbinil diminished the ratio of neointima to the media. Together, these observations suggest that, in vascular smooth muscle cells (VSMC), AR is a growth-responsive gene product and that inhibition of AR prevents VSMC growth and decreases intimal hyperplasia and restenosis.
Bhatnagar
A
A
Division of Cardiology, Department of Medicine, Jewish Cardiovascular Research Center, University of Louisville, 500 South Floyd Street, 40202, Louisville, KY, USA.
Ruef
J
J
Liu
S
S
Srivastava
S
S
Srivastava
S K
SK
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020212:Carotid Artery Injuries / Q000201:enzymology / Q000473:pathology; D002455:Cell Division; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D008934:Mitogens / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology*; D009281:Naphthalenes / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D008934:Mitogens; D009281:Naphthalenes; D012333:RNA, Messenger; C040550:tolrestat; D000449:Aldehyde Reductase; C026411:sorbinil