Diet-Induced Severe Hyperhomocysteinemia Promotes Atherosclerosis Progression and Dysregulates the Plasma Metabolome...

Area of Science:

• Biochemistry
• Cardiovascular Science
• Metabolomics

Background:

• Atherosclerosis and cardiovascular disease are leading causes of death.
• Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis, but underlying mechanisms are unclear.
• Homocysteine levels are influenced by B vitamins (B6, B9, B12) and methyl donors.

Purpose of the Study:

• To investigate the biological influence of HHcy on atherosclerosis development and progression.
• To identify metabolic changes associated with HHcy-induced atherogenesis.

Main Methods:

• Apolipoprotein-E-deficient mice (a model for atherosclerosis) were fed a hyperhomocysteinemic diet (HHD) or control diet (CD) for eight weeks.
• Quantified plasma, aorta, and liver methylation metabolites.
• Performed broad targeted metabolomic analysis of plasma and quantified aortic plaque burden using MRI.

Main Results:

• HHD induced severe accumulation of homocysteine and increased aortic plaque burden, confirming atherogenic effects.
• Decreased plasma and aortic methylation capacity (SAM:SAH ratio) and increased aortic cystathionine flux were observed in HHD mice.
• HHD mice showed decreased hepatic betaine and choline, and widespread plasma metabolome alterations, including lipids and amino acids.

Conclusions:

• Severe HHcy significantly promotes vascular plaque progression.
• HHcy impacts methylation capacity and transsulfuration pathway flux.
• Dysfunctional lipid metabolism and altered amino acid profiles are associated with HHcy-induced atherosclerosis, suggesting novel pathophysiological pathways.