Homocysteine Theory of Arteriosclerosis

文男, 葛谷; 徳, 吉峯; 邦雄, 森; 信夫, 坂本

doi:10.5551/jat1973.6.2_135

Cited by 2 publications

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“…These findings were confirmed in baboons, pigs, and monkeys (44)(45)(46). The arteriosclerotic plaques in these animals are principally of the fibrous and fibrocalcific type.…”

Section: Homocysteine Theory Of Arteriosclerosissupporting

confidence: 71%

Hyperhomocysteinemia and arteriosclerosis: historical perspectives

McCully

2005

Clinical Chemistry and Laboratory Medicine (CCLM)

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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.

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“…These findings were confirmed in baboons, pigs, and monkeys (44)(45)(46). The arteriosclerotic plaques in these animals are principally of the fibrous and fibrocalcific type.…”

Section: Homocysteine Theory Of Arteriosclerosissupporting

confidence: 71%

Hyperhomocysteinemia and arteriosclerosis: historical perspectives

McCully

2005

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…Feeding rabbits a synthetic diet containing homocysteine thiolactone perchlorate, methionine, or homocysteine oxidized with hydrogen peroxide produced arteriosclerotic plaques, similar to those observed with parenteral administration, and scattered arterial and venous thrombi were also demonstrated. Parenteral pyridoxine prevented thrombosis from homocysteine or methionine injections, and these observations were confirmed in independent experiments (139).…”

Section: Homocysteine and Experimental Atherogenesissupporting

confidence: 67%

Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging

McCully

2015

Comprehensive Physiology

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The importance of homocysteine in vascular function and arteriosclerosis was discovered by demonstration of arteriosclerotic plaques in children with homocystinuria caused by inherited enzymatic deficiencies of cystathionine synthase, methionine synthase, or methylene-tetrahydrofolate reductase. According to the homocysteine theory of arteriosclerosis, an elevated blood homocysteine level is an important risk factor for atherosclerosis in subjects without these rare enzymatic abnormalities. The homocysteine theory is supported by demonstration of arterial plaques in experimental animals with hyperhomocysteinemia, by discovery of a pathway for conversion of homocysteine thiolactone to sulfate in cell cultures from children with homocystinuria, and by demonstration of growth promotion by homocysteic acid in normal and hypophysectomized animals. Studies with cultured malignant cells revealed abnormal homocysteine thiolactone metabolism, resulting in homocysteinylation of proteins, nucleic acids, and glycosaminoglycans, explaining the abnormal oxidative metabolism, abnormalities of cellular membranes, and altered genetic expression observed in malignancy. Abnormal homocysteine metabolism in malignant cells is attributed to deficiency of thioretinamide, the amide synthesized from retinoic acid and homocysteine thiolactone. Two molecules of thioretinamide combine with cobalamin to form thioretinaco. Based on the molecular structure of thioretinaco, a theory of oxidative phosphorylation was proposed, involving oxidation to a disulfonium derivative by ozone, and binding of oxygen, nicotinamide adenine dinucleotide and phosphate as the active site of adenosine triphosphate synthesis in mitochondria. Obstruction of vasa vasorum by aggregates of microorganisms with homocysteinylated low-density lipoproteins is proposed to cause ischemia of arterial wall and a microabscess of the intima, the vulnerable atherosclerotic plaque.

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Homocysteine Theory of Arteriosclerosis

Cited by 2 publications

References 0 publications

Hyperhomocysteinemia and arteriosclerosis: historical perspectives

Hyperhomocysteinemia and arteriosclerosis: historical perspectives

Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging

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