Abstract
Inflammatory cytokine‐induced cell apoptosis is important for initiation and progression of chronic heart failure (CHF). Non‐coding RNAs, including long non‐coding RNAs and microRNAs, have emerged as critical regulators of this pathological process. The role in regulating inflammation and induction to cell apoptosis in CHF is not well understood. This study found CHF patients had elevated serum miR‐939‐5p, with greater increase in New York Heart Association (NYHA) I‐II patients than in NYHA III‐IV. Moreover, miR‐939‐5p was positively correlated with B‐type natriuretic peptide (BNP) in NYHA III‐IV patients, while not in NYHA I‐II. Further study showed miR‐939‐5p mimics promoted cell proliferation and inhibited inflammatory cytokine‐induced apoptosis of HUVECs and H9C2, while inhibition of endogenous miR‐939‐5p produced the opposite effects. Induced nitric oxide synthase (iNOS) and tumour necrosis factor α (TNFα) were identified as target genes of miR‐939‐5p. Additionally, lncRNA‐NOS2P3 acted as an endogenous sponge RNA to inhibit miR‐939‐5p expression, regulate the expression of iNOS/TNFα and control inflammation‐induced cells apoptosis. These suggest that CHF patients exhibited elevated serum miR‐939‐5p level especially in NYHA I‐II grades. And lnc‐NOS2P3‐miR‐939‐5p‐iNOS/TNFα pathway regulated inflammatory cytokine‐induced endothelial and myocardial cells apoptosis and provided a promising strategy for diagnosis and treatment of CHF.
Highlights
Inflammatory cytokines induced cells apoptosis is important for initiation and progression of chronic heart failure (CHF)
MiR-939-5p inhibited inflammation induced apoptosis of endothelial cells HUVECs and myocardial cells H9C2 Inflammatory cytokines induced cell apoptosis was the initial response to cardiac injury, which was important for cardiac remodeling contributing to CHF progression [4]
We observed that miR-939-5p mimic promoted and antagomir inhibited H9C2 myocytes proliferation by CCK8 assay (Fig. supplementary1A), and miR-939-5p regulated apoptosis of H9C2 cardiomyocytes the same as in HUVECs by western blot (Fig. supplementary1B) and FACS analysis (Fig. supplementary1C)
Summary
As more and more patients survive their initial cardiovascular diseases, chronic heart failure (CHF) becomes the leading cause of elderly hospitalization and death worldwide [1]. Inflammation activated Ca2+ independent inducible nitric oxide synthase (iNOS) will produce high level of NO, leads to apoptosis of myocardial and endothelial cells, and causes negative inotropic effect [21], and NO level in CHF patients was much higher [22]. Further study found slightly increased level of iNOS and TNFα in NYHA I-II grades CHF patients with no significance compared with normal controls, but was significantly up-regulation in NYHA III-IV patients [24]. Further we identified lncRNA-NOS2P3 could act as an endogenous sponge RNA to repress miR-939-5p and its target genes expression and regulate its inhibition to inflammation induced cells apoptosis. To identify target transcript and interacted lncRNAs of miRNA-939-5p, cells were transfected with miR-939 mimics (100 nM) for 36 h and total RNA was harvested. Data were considered significantly different if p-value
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