thiourea and Arteriosclerosis

Arsenic is atherogenic, carcinogenic, and genotoxic. Because atherosclerotic plaque has been considered a benign smooth muscle cell tumor, we have studied the effects of arsenite on DNA integrity of human vascular smooth muscle cells. By using single-cell alkaline electrophoresis, apparent DNA strand breaks were detected in a 4-hour treatment with arsenite at a concentration above 1 micromol/L. DNA strand breaks of arsenite-treated cells were increased by Escherichia coli formamidopyrimidine-DNA glycosylase and decreased by diphenylene iodinium, superoxide dismutase, catalase, pyruvate, DMSO, or D-mannitol. Extract from arsenite-treated cells showed increased capacity for producing superoxide when NADH was included in the reaction mixture; however, addition of arsenite to extract from untreated cells did not increase superoxide production. The superoxide-producing ability of arsenite-treated cells was also suppressed by diphenylene iodinium, 4,5-dihydroxy-1, 2-benzenedisulfonic acid disodium salt (Tiron), or superoxide dismutase. Superoxide production and DNA strand breaks in arsenite-treated cells were also suppressed by transfecting antisense oligonucleotides of p22phox, an essential component of NADH oxidase. Treatment with arsenite also increased the mRNA level of p22phox. These results suggest that arsenite activates NADH oxidase to produce superoxide, which then causes oxidative DNA damage. The result that arsenite at low concentrations increases oxidant levels and causes oxidative DNA damage in vascular smooth muscle cells may be important in arsenic-induced atherosclerosis.

Topics: Aorta; Arsenites; Arteriosclerosis; Cell Division; Cells, Cultured; Citrulline; DNA Damage; Enzyme Activation; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Humans; Membrane Transport Proteins; Multienzyme Complexes; Muscle, Smooth, Vascular; NADH, NADPH Oxidoreductases; NADPH Dehydrogenase; NADPH Oxidases; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxidative Stress; Phosphoproteins; Reactive Oxygen Species; RNA, Messenger; Teratogens; Thiourea; Transfection

Exposure of rabbits for 12 weeks to 300 ppm carbon disulfide (CS2) for 6 h/day, 5 days/week, or to 25 mg/day of thiourea or 2% cholesterol in the diet, or to any combination thereof caused a significant reduction in the concentration of serum thyroxine (T4). The reduction of the concentration of serum T4 in rabbits by the treatments was completely offset by the inclusion of 0.1 mg/day of sodium levothyroxine in the diet. Ingestion of feed containing 2% cholesterol significantly increased the degree of atherosclerosis present in the aortic arch and significantly increased the oil red O positive lipid present in the heart and the aorta, with the aortic arch being the most severely affected. The response of the aorta and the heart to the 2% cholesterol diet was not significantly modified by concurrent exposure to CS2 by inhalation or by treatment with thiourea, a metabolite of CS2. We found no evidence that the development of cardiovascular lesions induced by a 2% cholesterol diet in rabbits was mediated by a mechanism involving a component of hypothyroidism.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Azo Compounds; Carbon Disulfide; Cholesterol; Cholesterol, Dietary; Hemodynamics; Lipid Metabolism; Male; Myocardium; Rabbits; Thiourea; Thyroxine

Topics: Animals; Arteriosclerosis; Cholesterol; Dogs; Humans; Thiouracil; Thiourea

Topics: Animals; Arteriosclerosis; Cholesterol; Dogs; Humans; Thiouracil; Thiourea

Topics: Animals; Arteriosclerosis; Cholesterol; Dogs; Thiouracil; Thiourea