LncRNACOX2 Contributes To Cardiac Fibrosis Through LncRNACOX2-OSM-Stat3 Pathway In Mouse Radiation-induced Heart Disease

Abstract

Radiation-induced heart disease (RIHD) is a common side effect on patients who needed to be treated with chest radiation. It is reported that the most of final pathology of RIHD is cardiac fibrosis. Long noncoding RNAs (lncRNAs) have emerged as main regulators of cardiac diseases. However, few lncRNAs have been directly implicated in cardiac fibrosis caused by RIHD. The lncRNA expression were assessed by transcriptome data in cardiac tissues of irradiated mice with the heart dose of 16GY and sham-irradiated mice. The mechanisms and of lncRNA-COX2 in cardiac fibrosis were further investigated with both in vitro and in vivo models. We identified 214 differentially expressed lncRNAs in cardiac tissue of irradiated and sham-irradiated in mice. Among them, lncRNACOX2 was enriched in the nuclei of irradiated cardiac group. Knockdown of lncRNACOX2 prevented TGF-β-induced fibroblast-myofibroblast transition, and mended the impaired cardiac function in mice suffering RIHD. In vitro studies indicated that knockdown of lncRNACOX2 significantly inhibited the expression of transcription factor OSM. The OSM overexpression obviously disturbed the regulatory effects of lncRNACOX2 shRNAs in both the in vitro cultured cardiac fibroblasts. At the same time, OSM overexpression stimulated Stat3 increase. The lncRNACOX2 overexpression partially restrained the phenotype change of cardiac fibroblasts induced by OSM siRNAs. Our study identifies lncRNACOX2 as a critical regulator of cardiac fibrosis, and depended on lncRNACOX2-OSM-Stat3 pathway regulated cardiac fibrosis. Fibroblast-enriched lncRNACOX2 could represent a novel target biomarker for cardiac fibrotic in RIHD.