Homocysteine and the pathogenesis of atherosclerosis

Abstract

The homocysteine theory of arteriosclerosis was discovered by study of arteriosclerotic plaques occurring in homocystinuria, a disease caused by deficiencies of cystathionine synthase, methionine synthase or methylenetetrahydrofolate reductase. According to the homocysteine theory, metabolic and nutritional abnormalities leading to elevation of plasma homocysteine cause atherosclerosis in the general population without these rare enzymatic abnormalities. Through studies of metabolism of homocysteine thiolactone, the anhydride of homocysteine, in cell cultures from homocystinuric children, the pathway for synthesis of sulfate was found to be dependent upon thioretinamide, the amide formed from retinoic acid and homocysteine thiolactone. Two molecules of thioretinamide form the complex thioretinaco with cobalamin, and oxidative phosphorylation is catalyzed by reduction of oxygen, which is bound to thioretinaco ozonide, by electrons from electron transport particles. Atherogenesis is attributed to formation of aggregates of homocysteinylated lipoproteins with microorganisms, which obstruct the vasa vasorum during formation of arterial vulnerable plaques.

Keywords:

• atherosclerosis
• homocysteine
• lipoprotein
• microorganisms
• oxidative phosphorylation
• oxidative stress
• thioretinaco
• thioretinamide

Financial & competing interests disclosure

The preparation of this article was supported by the US Department of Veterans Affairs solely by salary. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The homocysteine theory was discovered by demonstration of arteriosclerotic plaques in children with homocystinuria caused by deficiencies of cystathionine synthase, methionine synthase or methylenetetrahydrofolate reductase.

• According to the homocysteine theory, metabolic and nutritional factors leading to hyperhomocysteinemia produce an increased risk of atherosclerosis, including coronary heart disease, stroke and peripheral vascular disease.

• Human observational studies have established hyperhomocysteinemia as a potent, independent risk factor for atherosclerosis in the general population.

• Studies with homocysteine thiolactone, the reactive cyclic anhydride of homocysteine, in cell cultures from children with cystathionine synthase deficiency and homocystinuria demonstrated a metabolic pathway for conversion of the sulfur atom of homocysteine to sulfate.

• Studies with cultured malignant cells revealed a metabolic blockade in conversion of the sulfur atom of homocysteine thiolactone to sulfate, resulting in homocysteinylation of free amino groups of proteins, nucleic acids and glycosaminoglycans, and causing aerobic glycolysis, altered genetic expression, diffuse membrane abnormalities and other phenotypic abnormalities of malignant cells.

• The blockade in synthesis of sulfate from homocysteine thiolactone is attributed to cellular deficiency of thioretinamide, the amide formed from retinoic acid and homocysteine thiolactone, and deficiency of thioretinaco ozonide, the complex formed from cobalamin, ozone, oxygen and thioretinamide which is responsible for ATP synthesis during oxidative phosphorylation, catalyzed by reduction of oxygen to water by electron transport.

• The active site of oxidative phosphorylation is proposed to comprise thioretinaco ozonide, oxygen, nicotinamide adenine dinucleotide and phosphate, which yields ATP, nicotinamide riboside and hydroperoxide upon reduction by electrons from electron transport complexes and a proton gradient across the F1Fl0 ATPase complexes of mitochondrial cristae.

• Homocysteine is a potent excitatory neurotransmitter that binds to the N-methyl-D-aspartate receptor, leading to oxidative stress, cytoplasmic calcium influx, apoptosis and endothelial dysfunction, the earliest manifestation of atherogenesis.

• The origin of arteriosclerotic vulnerable plaques is attributed to obstruction of the vasa vasorum by aggregates of homocysteinylated lipoproteins with microorganisms, leading to ischemia of arterial wall muscle cells, intramural cell death, hemorrhage, inflammation and an intimal microabscess, the vulnerable plaque.

• The declining US mortality rate from coronary heart disease and stroke since 1958 is partly attributed to fortification of processed foods by pyridoxine and folic acid, precursors of the coenzymes which activate homocysteine metabolism and prevent hyperhomocysteinemia.

• A metabolic and nutritional protocol consisting of whole nutritious foods, thioretinamide, B vitamins, ascorbic acid, vitamin D3, menoquinone, retinol, nicotinamide riboside, adenosyl methionine and pancreatic enzymes is suggested for therapy and prevention of diseases of aging associated with hyperhomocysteinemia, including arteriosclerosis, cancer, dementia, osteoporosis, neurodegenerative diseases, autoimmune diseases and the aging process.