Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model
Marion A. Hofmann, … , David M. Stern, Ann Marie Schmidt
Marion A. Hofmann, … , David M. Stern, Ann Marie Schmidt
Published March 15, 2001
Citation Information: J Clin Invest. 2001;107(6):675-683. https://doi.org/10.1172/JCI10588.
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Article

Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model

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.

Authors

Marion A. Hofmann, Evanthia Lalla, Yan Lu, Michelle Ryu Gleason, Bonnie M. Wolf, Nozomu Tanji, Luis J. Ferran Jr., Brigitte Kohl, Vijay Rao, Walter Kisiel, David M. Stern, Ann Marie Schmidt

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Figure 2

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HHcy enhances activation of NF-κB as seen using EMSA. (a) HUVECs were ex...
HHcy enhances activation of NF-κB as seen using EMSA. (a) HUVECs were exposed to BSA, L-HC, or L-cysteine (100 μM) for 8 hours. Nuclear extracts were prepared and subjected to EMSA. AP < 0.05 vs. lanes 1 and 3. In lane 4, a 100-fold molar excess of unlabeled NF-κB was added to indicate specificity for NF-κB. (b) After 8 weeks of diet, apoE-null mice were sacrificed and nuclear extracts prepared from kidney (lanes 1–3) or aorta (lanes 4–6) for EMSA. BP < 0.01 vs. lanes 1 and 3 and 4 and 6, respectively. EMSA was performed on n = 7 mice/diet; representative experiments are shown. Densitometric analysis was performed; pixels obtained from analysis of EMSA on BSA-treated samples or tissue samples from animals receiving diet A were arbitrarily assigned a relative value of 1.