Probucol Protects Arteries by Inhibiting Two-Electron Oxidant

Researchers studying coronary artery disease have found that inhibition of free radicals had little effect on preventing heart disease while treatment of two-electron oxidants retarded development of atherosclerosis.

While antioxidants such as beta-carotene and vitamin E have failed in clinical trials to protect against heart disease, the drug probucol had been found to slow the development of atherosclerosis in carotid arteries and restenosis of coronary arteries after angioplasty.

To determine probucol's mode of operation, investigators at the University of New South Wales (Sydney, AU) created laboratory models for three types of coronary artery disease. The models comprised apolipoprotein E–deficient mice, a model of atherosclerosis; rabbit aortic balloon injury, a model of restenosis; and carotid injury in obese Zucker rats, a model of type 2 diabetes. Animals in each group were treated with probucol, its sulfur-containing metabolite, or a sulfur-free phenolic analogue.

Results published in the April 10, 2006, online edition of the Journal of Experimental Medicine showed that probucol and its sulphur-containing metabolite, but not the sulphur-free phenolic analogue, protected the arteries via cell-specific effects on inhibiting macrophage accumulation, stimulating re-endothelialization, and inhibiting vascular smooth muscle cell proliferation. These effects were found to be mediated via induction of heme oxygenase-1 (HO-1), an activity not shared by vitamin E.

The authors concluded that, "Two-electron rather than radical [one-electron] oxidants are important contributors to atherogenesis, and point to novel lead compounds for therapeutic intervention against atherosclerotic diseases.”



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