Early concepts of the origin of arteriosclerosis were introduced in the 19th century by Rokitansky and Virchow, who described mural thrombosis, inflammatory damage to arterial intima, increased intimal permeability to plasma, mucoid degeneration of arterial wall, deposition of plasma lipids in plaques, and fibrosis and calcification of plaques. Experimental production of arteriosclerosis by feeding animal foods to rabbits was attributed to protein intoxication by Ignatowsky in 1908 and to dietary cholesterol by Anitschkow in 1913. Newburgh confirmed the protein hypothesis in 1915-1925 but failed to identify which amino acid produced plaques because methionine (1922) and homocysteine (1932) had not yet been discovered. Cases of homocystinuria from inherited deficiency of cystathionine synthase were found to be associated with thrombosis and vascular disease in 1964. The index case of methionine synthase deficiency (cobalamin C disease) was found by McCully in 1969 to be associated with arteriosclerosis, leading to the homocysteine theory of arteriosclerosis. The theory explains experimental arteriosclerosis by deficiency of vitamin B6 in monkeys, choline deficiency in rats, thyroid deficiency in rats, and methionine deficiency in monkeys. The thrombogenic and atherogenic effects of homocysteine were demonstrated in rabbits, baboons and other species, reproducing the pathological findings found in homocystinuria. Clinical and epidemiological studies in the past two decades have demonstrated that elevated plasma homocysteine is a potent independent risk factor for arteriosclerosis in the general population, supporting the validity of the theory.

Hyperhomocysteinemia and arteriosclerosis: historical perspectives.

Long term treatment of neonatal aortic smooth muscle cells with βVLDL induces cholesterol accumulation

Apolipoprotein E expression in aortic smooth muscle cells: the effect of beta VLDL.

A quantitative method for analysis of radiolabelled proteoglycans synthesized by cultured human arterial smooth muscle cells

The acidic glycosaminoglycans in urine, serum and myocardial tissue of aged patients with myocardial infarction have been analyzed by two-dimensional electrophoresis on cellulose acetate membranes in order to study the mechanism of repair of myocardium after infarction. Patients tested 4 years or more after infarction showed excretion of urinary glycosaminoglycans within the range normally encountered for the aged. However, in cases of acute myocardial infarction, the excretion of glycosaminoglycans was found to be increased 3 to 4 times in the early acute phase and then gradually to decrease to within the normal range during recovery. A significant increase in excretion of low sulfated chondroitin sulfate was observed in the acute phase. Low sulfated chondroitin sulfate was the major glycosaminoglycan in sera from the patients, regardless of stages. In normal myocardial tissue, hyaluronic acid was the major component and heparan sulfate, chondroitin sulfate and dermatan sulfate were the minor components. In myocardium from patients with acute infarction, a decrease in heparan sulfate was observed, while in that of old infarction, dermatan sulfate was the main component and in advanced aneurysm, increase in chondroitin sulfate was observed along with dermatan sulfate. These findings suggest that the repair process of infarcted myocardium is very similar to that occurring during healing of hepatic fibrosis and damaged arterial walls.

J. Hausmann

Papers

Glycosaminoglycan content in neonatal rat aortic smooth muscle cell cultures