Inflammation Related lncNOS2P3-miR-939-5p-iNOS/TNFα Pathway Inhibits Myocardial and Endothelial Cells Apoptosis in Chronic Heart Failure

Background: Inflammatory cytokines induced cells apoptosis is important for initiation and progression of chronic heart failure (CHF). Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) were critical in this pathogenesis. However, their roles in inflammation and apoptosis of CHF remain unclear. Methods: Bioinformatics analysis and luciferase reporter assay was used to predict and verify pairs of lncRNA-miRNA-mRNA. RT-qPCR was used to evaluate the expression of lncRNA, miRNAs and mRNAs. CCK8 and flow cytometry were applied to determine cells vitality and apoptosis. Western blot was used for protein level analysis. Findings: CHF patients had elevated serum miR-939-5p, with greater increase in NYHA I-II patients than in NYHA III-IV. Moreover, miR-939-5p was positively correlated with BNP in NYHA III-IV patients, while not in NYHA I-II, suggesting that miR-939-5p might be an additional supplement for diagnosis of heart failure. Further study showed miR-939-5p mimic promoted proliferation and inhibited inflammatory cytokines induced apoptosis of HUVECs and H9C2, while inhibition of endogenous miR-939-5p by antagomir produced the opposite effects. INOS and TNFα were identified and confirmed as target genes of miR-939-5p. Moreover, we identified lncRNA-NOS2P3 as a sponge RNA to inhibit miR-939-5p expression, regulate the expression of iNOS/TNFα, and control inflammation induced myocardial and endothelial cells apoptosis. Interpretation: Together, CHF patients exhibited elevated serum miR-939-5p especially in NYHA I-II grades. Lnc-NOS2P3-miR-939-5p-iNOS/TNFα pathway played an important role in regulating inflammatory cytokines induced cells apoptosis and provided a promising strategy for diagnosis and treatment of CHF. Funding: National Natural Science Foundation of China, Foundation of Shanghai Municipal Health Commission, Project of Tongji University. Declaration of Interest: The authors declared that they have no conflict of interest. Ethical Approval: The Institutional Review Board of Tongji Medical School affiliated Shanghai East Hospital approved the study protocol and the written informed consent was obtained from each participant before any sample or data collection.