Cytotoxicity of oxidation derivatives of cholesterol on cultured aortic smooth muscle cells and their effect on cholesterol biosynthesis

Abstract

Aortic smooth muscle cell death is an important initial lesion of atherosclerosis. A number of autooxidation products of cholesterol which has been recognized recently has the capability of inducing rabbits' aortic smooth cell death in vitro. Twelve oxidation derivatives of cholesterol, available commercially, were dissolved in small amounts of ethanol, then added to the culture medium at levels not exceeding 0.8%. The medium contained 10% fetal calf's serum which served as an in situ vehicle for the sterols. The degrees of cytotoxicity were graded and measured as percentage of dying and dead cells in the cultures within 24 hr. 25-Hydroxycholesterol and cholesthan-3 beta, 5 alpha, 6 beta-triol, were the most toxic compounds among the sterols tested. When these oxidation derivatives of cholesterol were added to these cultured cells, they significantly depressed activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a regulatory enzyme of cholesterol biosynthesis (up to 83% inhibition by 25 hydroxycholesterol at a 3 microgram/ml concentration in culture medium) but the sequence of degree of inhibition was not exactly correlated with that of cytotoxicity. Various mechanisms are speculated. Purified cholesterol showed no cytotoxic effect and minimal inhibition of cholesterol biosynthesis.

Probucol Reduces Oxysterol Formation in Hypertensive Rabbits

“…[11][12][13][14][15][16] Because cholesterol oxides (ChOx) have been ubiquitously identified in human plasma and atheromatous lesions, their involvement in the atherogenic process is receiving increasing scrutiny. [17][18][19][20][21] ChOx may influence the atherogenic process in several ways, since they are cytotoxic toward the cellular components of the arterial wall, [22][23][24] increase vascular permeability, 25 promote cholesterol ester formation and accumulation, 26 -28 inhibit prostaglandin I 2 synthesis by endothelial cells, 29 and perturb cholesterol biosynthesis. 30,31 Previously, we and others have shown that cholesterol feeding of New Zealand White rabbits leads to increased plasma and aortic wall cholesterol oxide content, 7,32 which is reduced with the antioxidant agent probucol.…”

Neuroprotective Effects of Ginsenoside Rg3against 24-OH-cholesterol-induced Cytotoxicity in Cortical Neurons

“…An excessive amount of cholesterol oxides damages endothelial cells [8,9], smooth muscle cells [2,10], and fibroblasts [11,12], and accumulating evidence suggests that cholesterol oxides are toxic to neural cells in nerve growth factor-differentiated neuronal PC12 cells as a model for sympathetic neurons [13,14], cultured cerebellar granule cells [1], and microglial cells [15]. Although the molecular mechanisms by which cholesterol…”

Enhancement of MMP-9 Activity in THP-1 Cells by 7-ketocholesterol and Its Suppression by the HMG-CoA Reductase Inhibitor Fluvastatin

“…They are also reported to be present at relatively high concentrations in atherosclerotic plaques (4), and contribute to the development of atherosclerosis (5)(6)(7)(8)(9). We have reported that 7-ketocholesterol (7-KCHO), an oxysterol, induced the apoptosis and inhibited the migration (13) of human smooth muscle cells (SMC) (10)(11)(12).…”