Homocysteine Metabolites, Endothelial Dysfunction, and Cardiovascular Disease

Area of Science:

• Cardiovascular Science
• Biochemistry
• Molecular Biology

Background:

• Atherosclerosis and cardiovascular disease (CVD) are leading global causes of mortality, driven by inflammation and endothelial dysfunction.
• Hyperhomocysteinemia (HHcy), characterized by elevated homocysteine (Hcy) levels, is a significant risk factor for CVD.
• Endothelial dysfunction, the initial step in atherosclerosis, results from factors disrupting vascular homeostasis, including HHcy.

Purpose of the Study:

• To elucidate the mechanisms by which Hcy metabolites contribute to endothelial dysfunction, CVD, and stroke.
• To explore the role of epigenetic modifications in Hcy-induced vascular pathology.
• To identify potential therapeutic targets for Hcy-related vascular complications.

Main Methods:

• Review of epidemiological, biochemical, and clinical studies on homocysteine metabolism and CVD.
• Analysis of the biochemical modifications of proteins by Hcy metabolites (e.g., N-homocysteinylated proteins).
• Investigation of epigenetic mechanisms, including microRNAs and histone modifications, involved in Hcy-induced vascular damage.

Main Results:

• Elevated Hcy, Hcy-thiolactone, and N-Hcy-proteins promote endothelial dysfunction, inflammation, and pro-atherogenic changes.
• Hcy metabolites induce epigenetic alterations, including mTOR signaling upregulation and autophagy inhibition via microRNAs and histone modifications.
• Cystathionine and Hcy-thiolactone are linked to myocardial infarction and ischemic stroke through effects on blood clotting.

Conclusions:

• Hcy metabolites are key drivers of endothelial dysfunction and atherosclerosis, contributing to CVD and stroke.
• Epigenetic dysregulation plays a crucial role in the pathogenesis of Hcy-induced vascular disease.
• Targeting Hcy metabolism and its downstream effects presents a promising avenue for CVD prevention and treatment.