Copyright © 2005, European Society of Cardiology
Hyperhomocysteinemia inhibits post-injury reendothelialization in mice
aDepartment of Medicine, Baylor College of Medicine, United States
bDepartment of Pharmacology, Baylor College of Medicine, United States
cVA Medical Center, Houston, Texas 77030, United States
dSun Yat-sen University School of Medicine, Guangzhou, China
eMayo Clinic, Rochester, Minnesota 55905, United States
* Corresponding author. Houston VA Medical Center, Baylor College of Medicine, 2002 Holcombe Blvd. Houston, TX, 77030, United States. Tel.: +1 713 794 7568; fax: +1 713 794 7165. Email address: hongw{at}bcm.tmc.edu
Objective: Hyperhomocysteinemia (HHcy) is a risk factor for cardiovascular disease and has been reported to inhibit endothelial cell (EC) growth. Notwithstanding, precisely how HHcy regulates EC growth in vivo remains unknown. In this study, we established a mouse model of endothelial injury and reendothelialization and examined the role and mechanism of HHcy in endothelial repair.
Methods and results: A mouse model of carotid artery air-dry endothelium denudation and reendothelialization was established and used to evaluate post-injury endothelial repair in mice with the gene deletion of cystathionine-β-synthase (CBS). Moderate and severe HHcy were induced in CBS+/+ and CBS–/+ mice through a high-methionine diet. Post-injury reendothelialization, which correlated with increased post-injury neointima formation, was impaired in severe HHcy mice. To elucidate the underlying mechanism, we examined circulating endothelial progenitor cells (EPC) in HHcy mice and studied the effect of homocysteine (Hcy) on proliferation, migration, and adhesion of human umbilical vein endothelial cells (HUVEC). The peripheral EPC population was not significantly altered in HHcy mice. Hcy had a profound inhibitory effect on EC proliferation and migration at physiologically relevant concentrations and inhibited EC adhesion at concentrations of 200 µM and higher.
Conclusion: We have established a convenient and accurate mouse model of carotid injury in which the reendothelialization process can be precisely quantified. In addition, we have observed impaired reendothelialization and increased neointimal formation in severe HHcy mice. The capacity of Hcy to inhibit proliferation and migration of EC may be responsible for impaired reendothelialization and contribute to arteriosclerosis in HHcy.
KEYWORDS Homocysteine; Carotid injury; Reendothelialization
Time for primary review 28 days
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