Carvedilol, a pharmacological antioxidant, inhibits neointimal matrix metalloproteinase-2 and -9 in experimental atherosclerosis.

Abstract

Matrix metalloproteinase (MMP) is critical to the progression of atherosclerosis and neointima hyperplasia after vascular injury. We investigated the effects of carvedilol, a pharmacological antioxidant with alpha- and beta-adrenergic blocking activity, on MMP-2 and MMP-9 expression. Vascular injury was induced with the balloon catheters on abdominal aortas of high-cholesterol-fed rabbits. On Day 21, there was significant aortic neointima formation with increased oxidative DNA damage by immunostaining with 8-hydroxy-2'-deoxyguanosine and enhanced MMP-2 and MMP-9 expressions by Western blotting, which were significantly reduced by oral administration of carvedilol (20 mg/kg/day) or probucol (100 mg/kg/day). Vascular expression (by Western blot), activity (by gelatin zymography), and mRNA levels of MMP-2 and MMP-9 were also reduced by carvedilol or probucol. Besides, pretreatment with carvedilol or probucol but not propranolol, a beta-blocker, or prazocin, an alpha-blocker, inhibited tumor necrosis factor-alpha-stimulated expressions and activities of MMP-2 and MMP-9 in human aortic smooth muscle cells. On electrophoretic mobility-shift assay, carvedilol inhibited the binding activities of activator protein-1 and specific protein-1, two major transcription factors for MMP promoter regions. Accordingly, carvedilol, a pharmacological antioxidant, inhibited in vivo and in vitro expression of MMP-2 and MMP-9 properly by modulating the redox-related pathways, suggesting its potential clinical implications.

• Authors: Tao-Cheng Wu, Yung-Hsiang Chen, Hsin-Bang Leu, Yuh-Lien Chen, Feng-Yen Lin, Shing-Jong Lin, Jaw-Wen Chen
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 43 Issue 11 Pg. 1508-22 (Dec 01 2007) ISSN: 0891-5849 [Print] United States
• PMID: 17964422 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Carbazoles
• Matrix Metalloproteinase Inhibitors
• Propanolamines
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• Carvedilol
• 8-Hydroxy-2'-Deoxyguanosine
• Deoxyguanosine
• Probucol

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Animals
• Antioxidants (pharmacology)
• Aorta, Abdominal (enzymology)
• Atherosclerosis (drug therapy, physiopathology)
• Carbazoles (pharmacology)
• Carvedilol
• Cells, Cultured
• Deoxyguanosine (analogs & derivatives, biosynthesis)
• Diet, Atherogenic
• Humans
• Hyperplasia (prevention & control)
• Male
• Matrix Metalloproteinase Inhibitors
• Probucol (pharmacology)
• Propanolamines (pharmacology)
• RNA, Messenger (metabolism)
• Rabbits
• Tumor Necrosis Factor-alpha (pharmacology)
• Tunica Intima (drug effects, enzymology, pathology)