Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model

M A Hofmann; E Lalla; Y Lu; M R Gleason; B M Wolf; N Tanji; L J Ferran Jr; B Kohl; V Rao; W Kisiel; D M Stern; A M Schmidt

doi:10.1172/JCI10588

Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model

J Clin Invest. 2001 Mar;107(6):675-83. doi: 10.1172/JCI10588.

Authors

M A Hofmann¹, E Lalla, Y Lu, M R Gleason, B M Wolf, N Tanji, L J Ferran Jr, B Kohl, V Rao, W Kisiel, D M Stern, A M Schmidt

Affiliation

¹ College of Physicians and Surgeons, Columbia University, 630 W. 168th Street, P&S 17-501, New York, NY 10032, USA. mah81@columbia.edu

PMID: 11254667
PMCID: PMC208940
DOI: 10.1172/JCI10588

Abstract

Although hyperhomocysteinemia (HHcy) is a well-known risk factor for the development of cardiovascular disease, the underlying molecular mechanisms are not fully elucidated. Here we show that induction of HHcy in apoE-null mice by a diet enriched in methionine but depleted in folate and vitamins B6 and B12 increased atherosclerotic lesion area and complexity, and enhanced expression of receptor for advanced glycation end products (RAGE), VCAM-1, tissue factor, and MMP-9 in the vasculature. These homocysteine-mediated (HC-mediated) effects were significantly suppressed, in parallel with decreased levels of plasma HC, upon dietary supplementation with folate and vitamins B6/B12. These findings implicate HHcy in atherosclerotic plaque progression and stability, and they suggest that dietary enrichment in vitamins essential for the metabolism of HC may impart protective effects in the vasculature.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Apolipoproteins E / deficiency
Apolipoproteins E / genetics
Arteriosclerosis / etiology*
Arteriosclerosis / metabolism
Arteriosclerosis / pathology
Cells, Cultured
Diet
Disease Models, Animal
Folic Acid / administration & dosage
Humans
Hyperhomocysteinemia / complications*
Hyperhomocysteinemia / metabolism
Immunohistochemistry
Male
Matrix Metalloproteinase 9 / metabolism
Methionine / administration & dosage
Mice
Mice, Inbred C57BL
Mice, Knockout
Pyridoxine / administration & dosage
Receptor for Advanced Glycation End Products
Receptors, Immunologic / metabolism
Thromboplastin / metabolism
Vascular Cell Adhesion Molecule-1 / metabolism
Vasculitis / etiology*
Vasculitis / metabolism
Vasculitis / pathology
Vitamin B 12 / administration & dosage

Substances

Apolipoproteins E
Receptor for Advanced Glycation End Products
Receptors, Immunologic
Vascular Cell Adhesion Molecule-1
Thromboplastin
Folic Acid
Methionine
Matrix Metalloproteinase 9
Pyridoxine
Vitamin B 12