Deficiency of the MicroRNA-31–MicroRNA-720 Pathway in the Plasma and Endothelial Progenitor Cells From Patients With Coronary Artery Disease

Abstract

Objective-Defects in angiogenesis/vasculogenesis or vessel repair are major complications of coronary artery disease (CAD). Endothelial progenitor cells (EPCs) play a fundamental role in postnatal vascular repair and CAD. The role of microRNAs in CAD pathogenesis and their potential as biomarkers remain to be elucidated. Approach and Results-MicroRNA-31 (miR-31) level in both the plasma and EPCs of patients with CAD is found lower.miR-31 regulates EPC activities by targeting FAT atypical cadherin 4 and thromboxane A2 receptor, which show increased expression in CAD EPCs. Overexpressing miR-31 in CAD EPCs rescued their angiogenic and vasculogenic abilities both in vitro and in vivo. When exploring approaches to restore endogenous miR-31, we found that far-infrared treatment enhanced the expression of not only miR-31, but also miR-720 in CAD EPCs. miR-720, which was also decreased in EPCs and the plasma of patients with CAD, stimulated EPC activity by targeting vasohibin 1. The miR720-vasohibin 1 pair was shown to be downstream of FAT atypical cadherin 4, but not of thromboxane A2 receptor. FAT atypical cadherin 4 inhibited miR-720 expression via repression of the planar cell polarity signaling gene four-jointed box 1 (FJX1), which was required for miR-720 expression through a hypoxia-inducible factor 1, α subunit-dependent mechanism. Restoring miR-720 level strengthened activity of CAD EPCs. The miR-31-miR-720 pathway is shown critical to EPC activation and that downregulation of this pathway contributes to CAD pathogenesis. Circulating levels of miR-31, miR-720, and vasohibin 1 have the potential to allow early diagnosis of CAD and to act as prognosis biomarkers for CAD and other EPC-related diseases. In addition to the number of circulating EPCs present, the regulation of postnatal angiogenesis/vasculogenesis also depends on the activity of mobilized EPCs. 8 In addition to the effects of protein-coding genes, the expression of various different microRNAs (miRNAs, miRs) also plays a critical role in the clinical course of CAD. miRNAs are a class of endogenous, small, noncoding, single-stranded RNAs of ≈22 nucleotides in length. The mature miRNAs negatively regulate gene expression by targeting specific mRNAs for cleavage or translational repression. Detecting the levels of tissue miRNAs, as well as the levels of circulating miRNAs in body fluids, is considered to be a potential approach to identifying new disease biomarkers and novel drug targets. Conclusions-Manipulating9-11 Many proangiogenic and antiangiogenic miRNAs have been pinpointed. Examples such as miR-221 and miR-222, which are transcribed from the same miR-221/222 cluster, have been shown to be able to modulate the angiogenic properties of human umbilical vein endothelial cells by targeting c-Kit and endothelial NO synthase.12,13 miR-221/222 levels in EPCs are significantly higher in patients with CAD.14,15 miR-10a* and miR-21 are also known to modulate EPC senescence via the suppression of high-mobility group A2.16 miR-10b and miR-196b, on the cont...

The Red Cell Distribution Width is Strong Predictor for the in-Hospital Mortality of the CABG Patients

“…Endothelial progenitor cells are important step in the process of vascular repair and development of coronary artery disease (19). Increased RDW is also related to failure of vascular repair mechanisms as a result of increased inflammatory mediators that lead to decrease the number of endothelial progenitor stem cells (20).…”

MicroRNA-140 is elevated and mitofusin-1 is downregulated in the right ventricle of the Sugen5416/hypoxia/normoxia model of pulmonary arterial hypertension.

“…These findings indirectly suggest that the number of c-kit ϩ cells was presumably increased in the hypertrophic RV. MiR-31 inhibits apoptosis, stimulates growth-maturation, and promotes migration of c-kit ϩ endothelial progenitor cells (17,68). Furthermore there is an association between high levels of miR-31 and c-kit activation (27).…”

miR-31 Dysregulation in Cystic Fibrosis Airways Contributes to Increased Pulmonary Cathepsin S Production

“…miR-31 is one of the most highly expressed miRNAs present in human non-CF airway epithelial cells (33) and our data demonstrate that miR-31 expression was significantly decreased in CF airway epithelial cell lines and primary cells. Altered miR-31 expression has been reported in such diseases as cancer, psoriasis, coronary artery disease, and lupus (41)(42)(43)(44); however, the mechanisms of this dysregulation are poorly understood.…”