Carvedilol, a pharmacological antioxidant, inhibits neointimal matrix metalloproteinase-2 and -9 in experimental atherosclerosis.
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.
Wu
Tao-Cheng
TC
Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China.
Chen
Yung-Hsiang
YH
Leu
Hsin-Bang
HB
Chen
Yuh-Lien
YL
Lin
Feng-Yen
FY
Lin
Shing-Jong
SJ
Chen
Jaw-Wen
JW
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001012:Aorta, Abdominal / Q000201:enzymology; D050197:Atherosclerosis / Q000188:drug therapy / Q000503:physiopathology*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002478:Cells, Cultured; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D004036:Diet, Atherogenic; D006801:Humans; D006965:Hyperplasia / Q000517:prevention & control; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D011341:Probucol / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology
D000975:Antioxidants; D002227:Carbazoles; D061965:Matrix Metalloproteinase Inhibitors; D011412:Propanolamines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000077261:Carvedilol; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D011341:Probucol