COA-Cl (2-Cl-C.OXT-A) can promote coronary collateral development following acute myocardial infarction in mice

Toshiyuki Nishikido,Aya Shiraki,Junsuke Igarashi,Jun-Ichi Oyama,Ikuko Tsukamoto,Koichi Node

doi:10.1038/s41598-019-39222-1

Abstract

2-Cl-C.OXT-A (COA-Cl) is a novel nucleic acid analogue that promotes tube-forming activity of human umbilical vein endothelial cells (HUVEC) through vascular endothelial growth factor (VEGF). The development of coronary collateral circulation is critical to rescue the ischemic myocardium and to prevent subsequent irreversible ischemic injury. We evaluated whether COA-Cl can promote angiogenesis in ischemic tissue, reduce infarct size and preserve cardiac contractility in vivo. Mice received COA-Cl or placebo daily for three days after myocardial infarction (MI) by coronary ligation. The degree of angiogenesis in ischemic myocardium was assessed by staining endothelial cells and vascular smooth muscle cells, and measuring infarct size/area-at-risk. In mice treated with COA-Cl, enhanced angiogenesis and smaller infarct size were recognized, even given a similar area at risk. We observed increases in the protein expression levels of VEGF and in the protein phosphorylation level of eNOS. In addition, the heart weight to body weight ratio and myocardial fibrosis in COA-Cl mice were decreased on Day 7. Administration of COA-Cl after MI promotes angiogenesis, which is associated with reduced infarct size and attenuated cardiac remodeling. This may help to prevent heart failure due to cardiac dysfunction after MI.

Highlights

It has been recognized that collateral arteries tend to develop in ischemic vascular disease
On Day 3 after myocardial infarction (MI), infarct size (IS) was reduced significantly in the group treated with COA-Cl (COA-Cl group) compared with the group treated with saline (6.6 ± 0.6% versus 13.7 ± 1.6%, respectively; P < 0.01), and the area at risk (AAR), the ischemic area by LAD
We demonstrated that COA-Cl reduced infarct area and developed myocardial collateral vessels with activating angiogenic molecules such as vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), and matrix metalloproteinase (MMP)-9 in murine MI model which leads to suppressing inappropriate cardiac remodeling

Summary

Introduction

It has been recognized that collateral arteries tend to develop in ischemic vascular disease. It is known that coronary angiogenesis in the ischemic heart provides myocardial protective effects, potentially by reducing infarct size, subsequent myocardial dysfunction and incidence of arrhythmias. Our present study aimed to evaluate the angiogenic effect of COA-Cl after myocardial infarction (MI) in vivo, because expansion of collateral artery circulation in the ischemic myocardium leads to increased myocardial perfusion and eventual improvements in ventricular function.

Results

Conclusion