Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerosis is now well recognised as a chronic inflammatory process which may ultimately lead to myocardial infarction, stroke and peripheral vascular disease. The role of inflammation in the pathogenesis of atherosclerosis has lead to interest in developing therapies that target vascular inflammation. Leucocytes play a key role during atherosclerotic plaque development. Activated vascular endothelium expresses vascular cell adhesion cell molecule-1 (VCAM-1), a member of the adhesion molecule superfamily, to which monocytes and lymphocytes can bind. These inflammatory cells can then move through the endothelium by diapedesis and release cytokines and enzymes, important components in the progression of the lesion. Researchers have demonstrated that the extent of atherosclerotic lesions is significantly reduced in animal models with decreased VCAM-1 expression. VCAM-1 has therefore been identified as a potential anti-inflammatory therapeutic target, the hypothesis being that reduced expression of VCAM-1 will slow the development of atherosclerosis. Succinobucol (AGI-1067), an anti-oxidant compound also capable of inhibiting VCAM-1 gene expression, is an example of such an agent and is currently being investigated in a phase III cardiovascular end-point trial due to report in 2007. If the results are positive, further investigations should derive to what extent blockade of VCAM-1 by succinobucol, rather than its other effects, accounts for the reduction in vascular events.
 ...
PMID:Vascular cell adhesion molecule-1: a viable therapeutic target for atherosclerosis? 1739 45

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.
 ...
PMID:Succinobucol induces apoptosis in vascular smooth muscle cells. 2220 69