Succinobucol induces apoptosis in vascular smooth muscle cells.
Probucol inhibits the proliferation of vascular smooth muscle cells in vitro and in vivo, and the drug reduces intimal hyperplasia and atherosclerosis in animals via induction of heme oxygenase-1 (HO-1). Because the succinyl ester of probucol, succinobucol, recently failed as an antiatherogenic drug in humans, we investigated its effects on smooth muscle cell proliferation. Succinobucol and probucol induced HO-1 and decreased cell proliferation in rat aortic smooth muscle cells. However, whereas inhibition of HO-1 reversed the antiproliferative effects of probucol, this was not observed with succinobucol. Instead, succinobucol but not probucol induced caspase activity and apoptosis, and it increased mitochondrial oxidation of hydroethidine to ethidium, suggestive of the participation of H(2)O(2) and cytochrome c. Also, succinobucol but not probucol converted cytochrome c into a peroxidase in the presence of H(2)O(2), and succinobucol-induced apoptosis was decreased in cells that lacked cytochrome c or a functional mitochondrial complex II. In addition, succinobucol increased apoptosis of vascular smooth muscle cells in vivo after balloon angioplasty-mediated vascular injury. Our results suggest that succinobucol induces apoptosis via a pathway involving mitochondrial complex II, H(2)O(2), and cytochrome c. These unexpected results are discussed in light of the failure of succinobucol as an antiatherogenic drug in humans.
Centre for Vascular Research, Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
Robyn G
RG
Midwinter
Ghassan J
GJ
Maghzal
Joanne M
JM
Dennis
Ben J
BJ
Wu
Hong
H
Cai
Alexandr A
AA
Kapralov
Natalia A
NA
Belikova
Yulia Y
YY
Tyurina
Lan-Feng
LF
Dong
Levon
L
Khachigian
Jiri
J
Neuzil
Valerian E
VE
Kagan
Roland
R
Stocker
D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D042963:Electron Transport Complex II / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D011341:Probucol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D011817:Rabbits; D051381:Rats
D008665:Metalloporphyrins; D011524:Protoporphyrins; D045304:Cytochromes c; D006861:Hydrogen Peroxide; C032628:tin protoporphyrin IX; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D042963:Electron Transport Complex II; C505410:Casp3 protein, rat; D053148:Caspase 3; C471047:succinobucol; D011341:Probucol