MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1

American Journal of Physiology - Endocrinology and Metabolism - Tập 299 Số 1 - Trang E110-E116 - 2010
Ting Zhao1,2, Jian Li1, Alex F. Chen2
1Beijing Institute of Geriatrics, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
2Department of Surgery, Vascular Medicine Institute and McGowan Institute of Regenerative Medicine, University of Pittsburgh School of Medicine and Vascular Surgery Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; and

Tóm tắt

Endothelial progenitor cells (EPCs) play an important role in angiogenesis, which is essential for numerous physiological processes as well as tumor growth. Several microRNAs (miRNAs) have been reported to be involved in angiogenesis. MiR-34a, recently reported as a tumor suppressor, has been found to target silent information regulator 1 (Sirt1), leading to cell cycle arrest or apoptosis. However, the role of miR-34a in EPC-mediated angiogenesis was unknown. The present study tested the hypothesis that miR-34a inhibits EPC-mediated angiogenesis by inducing senescence via suppressing Sirt1. Bone marrow-derived EPCs from adult male Spraque-Dawley rats were used. Results of flow cytometry showed that EPCs after 7 days of culture expressed both stem cell markers CD34 and CD133 and endothelial cell markers VEGFR-2 (flk-1) and VE-cadherin. MiR-34a was expressed in normal EPCs, and overexpression of miR-34a via its mimic transfection significantly increased its expression and impaired in vitro EPC angiogenesis. MiR-34a overexpression led to a significantly increased EPC senescence, paralleled with an ∼40% Sirt1 reduction. Furthermore, knockdown of Sirt1 by its siRNA resulted in diminished EPC angiogenesis and increased senescence. Finally, overexpression of miR-34a increased the level of Sirt1 effector-acetylated forkhead box O transcription factors 1 (FoxO1), an effect mimicked in EPCs following Sirt1 knockdown. In conclusion, miR-34a impairs EPC-mediated angiogenesis by induction of senescence via inhibiting Sirt1.

Từ khóa


Tài liệu tham khảo

10.1007/s10456-009-9135-7

10.1038/nature02871

10.1126/science.275.5302.964

10.1016/S0092-8674(04)00045-5

10.1146/annurev.biochem.73.011303.073651

10.1038/nrm1616

10.1038/nature04478

10.1073/pnas.92.20.9363

10.1161/CIRCULATIONAHA.107.748236

10.1182/blood-2008-06-161794

10.1038/nature04483

10.1126/scisignal.252pe1

10.1016/j.bbrc.2008.09.086

10.1101/gad.1467506

10.1161/CIRCULATIONAHA.106.631465

10.1016/j.jacc.2004.12.074

10.1038/cdd.2009.56

10.1161/ATVBAHA.107.155960

10.1016/j.molmed.2009.02.001

10.1161/CIRCRESAHA.107.153916

10.1016/j.canlet.2008.09.035

10.4161/cc.7.16.6533

10.1002/jcp.21834

10.1073/pnas.0704329104

10.1161/CIRCULATIONAHA.109.864629

10.1038/leu.2008.377

10.1161/ATVBAHA.109.185694

10.1016/j.yjmcc.2007.08.008

10.4161/cc.7.14.6267

10.1101/gad.435107

10.1073/pnas.1534804100

10.1161/CIRCRESAHA.108.191270

10.1073/pnas.0707351104

10.1111/j.1582-4934.2008.00598.x

10.1002/mc.20484

10.1161/01.RES.0000137877.89448.78

10.1093/cvr/cvn156

10.1073/pnas.0801613105

10.4161/cc.8.5.7753

10.1038/sj.emboj.7600570

10.1182/blood-2008-08-172254

Thông tin
Thông tin xuất bản

American Journal of Physiology - Endocrinology and Metabolism

Tập 299 Số 1

E110-E116

Thông tin tác giả