Abstract
Hyperhomocystinemia (HHcy) is known as an independent risk factor for cardiovascular disease. Our previous study showed that ginsenoside Rb1, the major active constituent of ginseng, prevents homocysteine (Hcy)-induced endothelial damage. However, the role of ginsenoside Rb1 in Hcy-induced dysfunction in endothelial progenitor cells (EPCs) remains unknown. In the study, we found that ginsenoside Rb1 reversed the Hcy-induced impairment of adhesive and migratory ability in EPCs which were significantly abolished by CXCR4 antagonist AMD3100 and VEGFR2 inhibitor SU5416. Ginsenoside Rb1 significantly reversed Hcy-induced SDF-1 reduction in the supernatant and in the serum. Ginsenoside Rb1 reversed downregulation of SDF-1 and VEGFR2 protein expression, inhibition of p38MAPK phosphorylation induced by Hcy. Re-endothelialization in balloon-injured carotid arteries significantly increased with EPCs transplant, and was even better with Rb1 treatment. This effect was significantly abolished by AMD3100. AMD3100 also decreased the number of CM-DiI labeled EPCs in injured arteries. Here we show for the first time that Rb1 prevents Hcy-induced EPC dysfunction via VEGF/p38MAPK and SDF-1/CXCR4 activation. These findings demonstrate a novel mechanism of the action of Rb1 that may have value in prevention of HHcy associated cardiovascular disease.
Highlights
Hyperhomocystinemia (HHcy) has been recognized as an independent risk factor for atherosclerosis since 19691
Rb1 reversed the downregulation of Stromal cell-derived factor-1 (SDF-1) and vascular endothelial growth factor receptor-2 (VEGFR2) induced by Hcy. These results indicate that the upregulation of SDF-1 and VEGFR2 were involved in the Rb1-induced increase of Endothelial progenitor cells (EPCs) adhesion and migration
We show for the first time that Rb1 prevents Hcy-induced EPC dysfunction via Vascular endothelial growth factor (VEGF)/p38 mitogen-activated protein kinase (p38MAPK) and SDF-1/CXCR4 activation
Summary
Hyperhomocystinemia (HHcy) has been recognized as an independent risk factor for atherosclerosis since 19691. Cytokine and vascular endothelial growth factors released at the site of injury promote EPCs from bone marrow to peripheral blood, which subsequently migrate to the injured site and differentiate into mature endothelial cells, leading to re-endothelialization and neovascularization[6]. A reduction in the expression of vascular endothelial growth factor receptor-2 (VEGFR2) was shown in high Hcy level mice[11] and VEGF/VEGFR inhibition was involved in Hcy-impaired angiogenesis[12]. Our previous study has showed that ginsenoside Rb1 via PI3K/Akt activation and PKC inhibition, prevents HUVECs from undergoing Hcy-induced endothelial dysfunction[18]. We hypothesize that VEGF/p38MAPK and SDF-1/CXCR4 activation be involved in the protective effect of ginsenoside Rb1 on Hcy-induced endothelial progenitor cell dysfunction
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