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(Circulation. 2008;118:2166-2173.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

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

Chao-Yung Wang, MD; Ming-Shien Wen, MD; Hong-Wei Wang, MD, PhD; I-Chang Hsieh, MD; Yuxin Li, MD, PhD; Ping-Yen Liu, MD, PhD; Fun-Chung Lin, MD; James K. Liao, MD

From the Vascular Medicine Research Unit, Brigham and Women’s Hospital and Harvard Medical School, Cambridge, Mass (C.-Y.W., H.-W.W., Y.L., P.-Y.L., J.K.L.), and Second Section of Cardiology, Department of Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan (C.-Y.W., M.-S.W., I.-C.H., F.-C.L.).

Correspondence to James K. Liao, MD, Brigham and Women’s Hospital, 65 Landsdowne St, Room 275, Cambridge, MA 02139. E-mail jliao{at}rics.bwh.harvard.edu

Received May 5, 2008; accepted September 16, 2008.

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 Per2^m/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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 118: 2115-2116. [Extract] [Full Text]