Dysregulated miR-361-5p/VEGF axis in the plasma and endothelial progenitor cells of patients with coronary artery disease

Hsei-Wei Wang; Hung-Hao Lo; Ya-Lin Chiu; Shing-Jyh Chang; Po-Hsun Huang; Ko-Hsun Liao; Cheng-Fong Tasi; Chun-Hsien Wu; Tsung-Neng Tsai; Cheng-Chung Cheng; Shu-Meng Cheng

doi:10.1371/journal.pone.0098070

Dysregulated miR-361-5p/VEGF axis in the plasma and endothelial progenitor cells of patients with coronary artery disease

PLoS One. 2014 May 27;9(5):e98070. doi: 10.1371/journal.pone.0098070. eCollection 2014.

Authors

Affiliations

¹ Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan; Genome Research Center & Cancer Research Center, National Yang-Ming University, Taipei, Taiwan; Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan; Department of Education and Research, Taipei City Hospital, Taipei, Taiwan.
² Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
³ Department of Obstetrics and Gynecology, Hsin-Chu Mackay Memorial Hospital, Hsin-Chu, Taiwan.
⁴ School of Medicine, National Yang-Ming University, Taipei, Taiwan; Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
⁵ Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.
⁶ Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Abstract

Dysfunction and reduction of circulating endothelial progenitor cell (EPC) is correlated with the onset of cardiovascular disorders including coronary artery disease (CAD). VEGF is a known mitogen for EPC to migrate out of bone marrow to possess angiogenic activities, and the plasma levels of VEGF are inversely correlated to the progression of CAD. Circulating microRNAs (miRNAs) in patient body fluids have recently been considered to hold the potential of being novel disease biomarkers and drug targets. However, how miRNAs and VEGF cooperate to regulate CAD progression is still unclear. Through the small RNA sequencing (smRNA-seq), we deciphered the miRNome patterns of EPCs with different angiogenic activities, hypothesizing that miRNAs targeting VEGF must be more abundant in EPCs with lower angiogenic activities. Candidates of anti-VEGF miRNAs, including miR-361-5p and miR-484, were enriched in not only diseased EPCs but also the plasma of CAD patients. However, we found out only miR-361-5p, but not miR-484, was able to suppress VEGF expression and EPC activities. Reporter assays confirmed the direct binding and repression of miR-361-5p to the 3'-UTR of VEGF mRNA. Knock down of miR-361-5p not only restored VEGF levels and angiogenic activities of diseased EPCs in vitro, but further promoted blood flow recovery in ischemic limbs of mice. Collectively, we discovered a miR-361-5p/VEGF-dependent regulation that could help to develop new therapeutic modalities not only for ischemia-related diseases but also for tumor angiogenesis.

Publication types

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

MeSH terms

Animals
Apoptosis
Case-Control Studies
Cell Movement
Cell Proliferation
Cells, Cultured
Coronary Artery Disease / blood
Coronary Artery Disease / genetics
Coronary Artery Disease / pathology*
Endothelial Progenitor Cells / metabolism
Endothelial Progenitor Cells / pathology*
Humans
Immunoenzyme Techniques
Ischemia / etiology
Ischemia / metabolism
Ischemia / pathology*
Mice
Mice, Nude
MicroRNAs / genetics*
Neovascularization, Physiologic*
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism*

Substances

MIRN361 microRNA, human
MicroRNAs
RNA, Messenger
VEGFA protein, human
Vascular Endothelial Growth Factor A

Grants and funding

This work was supported by National Science Council [NSC; NSC101-2320-B-010-059-MY3, NSC101-2627-B-010-003 and NSC101-2321-B-010-011], Tri-Service General Hospital [TSGH-C102-027], Veterans General Hospitals University System of Taiwan (VGHUST) Joint Research Program, Tsou's Foundation [VGHUST103-G7-2-3], National Health Research Institutes [NHRI-EX102-10254SI], Taipei City Hospital [10201-62-070], and National Yang-Ming University [Ministry of Education, Aim for the Top University Plan]. This work was also support in part by the UST-UCSD International Center for Excellence in Advanced Bioengineering sponsored by the Taiwan NSC I-RiCE Program [NSC102-2911-I-009-101]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.