Period2 deficiency blunts hypoxia-induced mobilization and function of endothelial progenitor cells

Tao Qin; Yuan-Yuan Sun; Wen-Wu Bai; Bo Wang; Yi-Fan Xing; Yan Liu; Rui-Xue Yang; Yu-Xia Zhao; Jian-Min Li

doi:10.1371/journal.pone.0108806

Period2 deficiency blunts hypoxia-induced mobilization and function of endothelial progenitor cells

PLoS One. 2014 Sep 30;9(9):e108806. doi: 10.1371/journal.pone.0108806. eCollection 2014.

Authors

Tao Qin¹, Yuan-Yuan Sun², Wen-Wu Bai³, Bo Wang³, Yi-Fan Xing³, Yan Liu⁴, Rui-Xue Yang⁴, Yu-Xia Zhao³, Jian-Min Li⁵

Affiliations

¹ Department of Emergency Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China.
² Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Jinan, Shandong, China; Department of Traditional Chinese Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China.
³ Department of Traditional Chinese Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China.
⁴ Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Jinan, Shandong, China.
⁵ Department of Orthopedics, Qilu Hospital, Shandong University, Jinan, Shandong, China.

Abstract

Background: In the clinic, variations in circadian rhythm are evident in patients with cardiovascular disease, and the risk of cardiovascular events increases when rhythms are disrupted. In this study, we focused on the role of the circadian gene period2 (per2) in mobilization and function of endothelial progenitor cells (EPCs) in vitro and in vivo after myocardial infarction (MI) in mice.

Methods and results: MI was produced by surgical ligation of the left anterior descending coronary artery in mice with and without per2 deficiency. Trans-thoracic echocardiography was used to evaluate cardiac function in mice. Per2-/- mice with MI showed decreased cardiac function and increased infarct size. The number of CD34+ cells and capillary density were decreased in the myocardium of per2-/- mice on immunohistochemistry. Flow cytometry revealed decreased number of circulating EPCs in per2-/- mice after MI. In vitro, per2-/- EPCs showed decreased migration and tube formation capacity under hypoxia. Western blot analysis revealed inhibited activation of extracellular signal-regulated kinase and Akt signaling in the bone marrow of per2-/- mice and inhibited PI3K/Akt expression in per2-/- EPCs under hypoxia.

Conclusions: Per2 modulates EPC mobilization and function after MI, which is important to recovery after MI in mice.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Marrow Cells / metabolism
Cell Hypoxia*
Cell Movement
Cells, Cultured
Endothelial Progenitor Cells / cytology
Endothelial Progenitor Cells / metabolism*
Extracellular Signal-Regulated MAP Kinases / metabolism
Immunohistochemistry
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardial Infarction / metabolism
Myocardial Infarction / pathology
Myocardium / metabolism
Myocardium / pathology
Period Circadian Proteins / genetics
Period Circadian Proteins / metabolism*
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction

Substances

Per2 protein, mouse
Period Circadian Proteins
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Extracellular Signal-Regulated MAP Kinases

Grants and funding

This study was supported by the National 973 Basic Research Program of China (no. 2012CB518603), National Natural Science Foundation of China (no's. 30873325, 81100103, 81173251, 81302939), Natural Science Foundation of Shandong Province (no's. ZR2011HQ020, ZR2009CM049), postdoctoral special foundation for innovative projects of Shandong Province (No. 201103049) and promotive research fund for excellent young and middle-aged scientists of Shandong Province (BS2013YY015). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.