Increased Vascular Senescence and Impaired Endothelial Progenitor Cell Function Mediated by Mutation of Circadian Gene Per2

Article

关键词: HUMAN BONE-MARROW;    IN-VIVO;    TUMOR SUPPRESSION;    LIFE-SPAN;    MYOCARDIAL-INFARCTION;    MICE LACKING;    CLOCK GENES;    AKT;    EXPRESSION;    GROWTH;   

DOI  :  10.1161/CIRCULATIONAHA.108.790469

来源: SCIE

【 摘 要 】

Background-Alteration of the circadian rhythm and increased vascular senescence are linked to cardiovascular disease. Per2, a circadian gene, is known to regulate endothelium-dependent vasomotion. However, the mechanism by which Per2 affects endothelial function is unknown. We hypothesize that endothelial dysfunction in Per2 mutant (Per2(m/m)) mice is mediated in part by increased vascular senescence and impaired endothelial progenitor cell (EPC) function. Methods and Results-Endothelial cells from Per(2m/m) mice exhibit increased protein kinase Akt signaling, greater senescence, and impaired vascular network formation and proliferation. Indeed, Per2(m/m) mice have impaired blood flow recovery and developed autoamputation of the distal limb when subjected to hind-limb ischemia. Furthermore, matrigel implantation into Per2(m/m) mice resulted in less neovascularization. Because EPCs contribute to angiogenesis, we studied the role of Per2 in these cells using bone marrow transplantation. Basal EPC levels were similar between wild-type and Per2(m/m) mice. However, compared with wild-type bone marrow transplantation mice, EPC mobilization was impaired in Per2(m/m) bone marrow transplantation mice in response to ischemia or VEGF stimulation. Bone marrow transplantation or infusion of wild-type EPC restored blood flow recovery and prevented autoamputation in Per2(m/m) mice. Conclusion-These findings indicate that mutation of Per2 causes Akt-dependent senescence and impairs ischemia-induced revascularization through the alteration of EPC function. (Circulation. 2008; 118: 2166-2173.)

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