Homocysteine and the pathogenesis of atherosclerosis

Area of Science:

• Biochemistry
• Cardiovascular Science
• Metabolic Disorders

Background:

• The homocysteine theory of arteriosclerosis links elevated plasma homocysteine to atherosclerosis.
• Homocystinuria, a rare genetic disorder, involves deficiencies in enzymes like cystathionine synthase, methionine synthase, or methylenetetrahydrofolate reductase, leading to homocysteine accumulation.
• This theory extends to the general population, suggesting metabolic and nutritional factors elevate homocysteine and cause atherosclerosis.

Purpose of the Study:

• To investigate the metabolic pathway of homocysteine thiolactone in cell cultures.
• To elucidate the role of homocysteine metabolism in sulfate synthesis.
• To understand the mechanisms underlying atherogenesis attributed to homocysteine.

Main Methods:

• Studied homocysteine thiolactone metabolism in cell cultures derived from homocystinuric children.
• Investigated the formation of thioretinamide from retinoic acid and homocysteine thiolactone.
• Examined the thioretinaco-cobalamin complex and its role in oxidative phosphorylation.

Main Results:

• Identified a pathway for sulfate synthesis dependent on thioretinamide, formed from retinoic acid and homocysteine thiolactone.
• Demonstrated that two thioretinamide molecules form a complex (thioretinaco) with cobalamin.
• Proposed that atherogenesis results from homocysteinylated lipoprotein aggregates with microorganisms obstructing the vasa vasorum, leading to arterial plaques.

Conclusions:

• Homocysteine metabolism is intricately linked to sulfate synthesis via thioretinamide and cobalamin complexes.
• Elevated homocysteine contributes to atherogenesis through the formation of obstructive lipoprotein-microorganism aggregates.
• The findings support and expand upon the homocysteine theory of arteriosclerosis.