Homocysteine accelerates senescence and reduces proliferation of endothelial progenitor cells.
Our previous studies showed that homocysteine (Hcy) reduces endothelial progenitor cell (EPC) numbers and impairs functional activity. However, the mechanisms by which Hcy reduces EPCs numbers and activity remain to be determined. Recent studies have demonstrated that reduced EPCs numbers and activity was associated with EPCs senescence which involved telomerase activity. Therefore, we investigated whether Hcy accelerates the onset of EPCs senescence through telomerase inactivation, leading to cellular dysfunction. EPCs were isolated from peripheral blood and characterized. After ex vivo cultivation, EPCs became senescent as determined by acidic beta-galactosidase staining. Hcy dose-dependently accelerated the onset of EPCs senescence in culture. Moreover, Hcy decreased proliferation of EPCs as assessed by BrdU incorporation assay and colony-forming capacity. To get further insights into the underlying mechanisms of these effects induced by Hcy, we measured telomerase activity and determined the phosphorylation of Akt by using western blot. Hcy significantly diminished telomerase activity and Akt phosphorylation. Taken together, the results of the present study demonstrated that Hcy accelerated the onset of EPCs senescence, leading to cellular dysfunction. The effect of Hcy might be dependent on telomerase inactivation, and Akt dephosphorylation also appeared to play a major role. In addition, atorvastatin had a preventative effect against Hcy-induced EPCs senescence.
Zhu
J H
JH
Department of Cardiology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Chen
J Z
JZ
Wang
X X
XX
Xie
X D
XD
Sun
J
J
Zhang
F R
FR
D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D049109:Cell Proliferation; D016922:Cellular Senescence; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology*; D006710:Homocysteine / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D010766:Phosphorylation; D013234:Stem Cells / Q000166:cytology*; D019098:Telomerase / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D006710:Homocysteine; D019098:Telomerase; D001616:beta-Galactosidase; D001973:Bromodeoxyuridine