The Production of Atherosclerosis in Rabbits by Feeding Diets Rich in Meat

Newburgh, L. H.; Clarkson, Sarah

doi:10.1001/archinte.1923.00110170033003

Cited by 59 publications

(8 citation statements)

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“…Extensive studies of dietary protein in experimental atherogenesis concluded that high concentrations of dietary protein are atherogenic in animals, confirming the observations of Ignatowsky and Newburgh (8,11,27). Substituting soy protein for casein in experimental diets inhibits atherogenesis (28).…”

Section: Hyperhomocysteinemia and Experimental Atherogenesissupporting

confidence: 75%

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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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Section: Hyperhomocysteinemia and Experimental Atherogenesissupporting

confidence: 75%

“…He and his colleagues repeated Ignatowsky's experiments using meat protein from which all cholesterol and fats were removed by extraction with organic solvents (11). This protein powder produced identical arterial plaques to those observed by Ignatowsky.…”

Section: Experimental Atherogenesismentioning

confidence: 80%

Hyperhomocysteinemia and arteriosclerosis: historical perspectives

McCully

2005

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…Influential early reviews 25,26 of studies involving several thousand rabbits concluded that spontaneous disease does occur, but that it consists almost exclusively of localized areas of medial thinning and calcification. These lesions bear some resemblance to Monckeberg's sclerosis of human arteries but not to the changes seen in atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Contrasting Patterns of Spontaneous Aortic Disease in Young and Old Rabbits

Barnes

Weinberg

1998

ATVB

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Abstract-The pattern of spontaneous lipid deposition around aortic branch ostia was mapped in New Zealand White rabbits aged 1 month or 2 to 6 years. The young rabbits were studied within 1 day of weaning, and the older rabbits had been maintained on a low-protein, low-fat diet. Plasma concentrations of total cholesterol for the two groups averaged 75 and 18 mg/dL, respectively. Aortas were fixed in situ at a pressure of 90 to 100 cm H 2 O, stained with oil red O, and photographed en face under an epifluorescence microscope. Areas of staining contrasted in color with the fixativestimulated autofluorescence of nondiseased tissue and were mapped by placing grids over the photomicrographs. Disease around intercostal ostia was rare, but two distributions were established by combining data from many branches. In weanlings, staining was seen within a triangular area downstream of the branch. In old animals, this area had the lowest frequency of disease; lesions tended to occur downstream of the spared region, along axes lying to either side of it, and at the lateral and upstream margins of the ostium. Disease was less rare at celiac branches. It occurred mainly downstream of the ostium in weanlings, whereas upstream sites were most affected in old animals, although significant disease remained at the juvenile locations. Earlier reports have described similar age-related distributions of disease in human aortas, consistent with a common underlying mechanism. The distributions also correlate with the spatial variations in arterial transport properties established in previous studies, and may be determined by them. (Arterioscler Thromb Vasc Biol. 1998;18:300-308.)

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“…High concentrations of dietary protein are atherogenic in experimental animals (106,203,223), and soy protein prevents experimental atherogenesis (101), possibly because of its low concentration of methionine. A synthetic diet containing soy protein and cholesterol produces arteriosclerosis in monkeys, and atherogenesis is inhibited in this model by added methionine in the diet (162).…”

Section: Homocysteine and Experimental Atherogenesismentioning

confidence: 99%

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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The Production of Atherosclerosis in Rabbits by Feeding Diets Rich in Meat

Cited by 59 publications

References 1 publication

Hyperhomocysteinemia and arteriosclerosis: historical perspectives

Hyperhomocysteinemia and arteriosclerosis: historical perspectives

Contrasting Patterns of Spontaneous Aortic Disease in Young and Old Rabbits

Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging

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