Abstract
The protective effects of downregulated miR-199a-5p on ischemic and hypoxic cardiomyocytes were well recognized, but the underlying mechanism of inhibited miR-199a-5p is not yet clear. The present study explored the relationship between enhanced signal transducer and activator of transcription 3 (STAT3) signaling and lowered production of miR-199a-5p in hypoxic cardiomyocytes. This study firstly found the correlation between elevated interleukin (IL)-6 and IL-11, as well as subsequent STAT3 signaling activation and the downregulation of miR-199a-5p in hypoxic myocardial samples from children with congenital heart disease. Then, using model of hypoxic mice and the intervention of phosphorylated STAT3 (pSTAT3), it was observed that pSTAT3 affected the expression of miR-199a-5p and modulated the expression of its target genes, including endoplasmic reticulum stress (ERS)-related activating transcription factor 6 (ATF6) and 78 kDa glucose-regulated protein (GRP78). Further observation revealed that the pSTAT3 signal in cardiac tissue could affect the expression of pri-miR-199a-2, a precursor of miR-199a-5p. And the chromatin immunoprecipitation (ChIP) assay also confirmed that pSTAT3 could bind to the promoter region of miR-199a-2 gene, which is more significant under hypoxic conditions. In conclusion, the activation of STAT3 signaling in cardiomyocytes during chronic hypoxia leads to downregulation of miR-199a-5p, which promotes the expression of many downstream target genes. This is an important pathway in the adaptive protection mechanism of myocardium during hypoxia.
Keywords:
Cardiomyocytes; Hypoxia; STAT3; Unfolded protein response; miR-199a-5p; microRNA.
MeSH terms
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Activating Transcription Factor 6 / genetics
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Activating Transcription Factor 6 / metabolism
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Adolescent
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Animals
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Arteriovenous Fistula / genetics*
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Arteriovenous Fistula / metabolism
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Arteriovenous Fistula / pathology
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Arteriovenous Fistula / surgery
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Cardiopulmonary Bypass
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Child
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Child, Preschool
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Disease Models, Animal
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Endoplasmic Reticulum Chaperone BiP
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Female
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Gene Expression Regulation
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Heart Defects, Congenital / genetics*
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Heart Defects, Congenital / metabolism
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Heart Defects, Congenital / pathology
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Heart Defects, Congenital / surgery
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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Humans
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Hypoxia / genetics*
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Hypoxia / metabolism
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Hypoxia / pathology
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Interleukin-11 / genetics
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Interleukin-11 / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Male
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Mice, Inbred BALB C
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Myocardium / metabolism
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Myocardium / pathology
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Myocytes, Cardiac / metabolism*
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Myocytes, Cardiac / pathology
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Promoter Regions, Genetic
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Pulmonary Artery / abnormalities*
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Pulmonary Artery / metabolism
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Pulmonary Artery / pathology
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Pulmonary Artery / surgery
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Pulmonary Veins / abnormalities*
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Pulmonary Veins / metabolism
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Pulmonary Veins / pathology
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Pulmonary Veins / surgery
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STAT3 Transcription Factor / genetics*
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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Tetralogy of Fallot / genetics*
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Tetralogy of Fallot / metabolism
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Tetralogy of Fallot / pathology
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Tetralogy of Fallot / surgery
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Unfolded Protein Response
Substances
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ATF6 protein, human
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Activating Transcription Factor 6
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Endoplasmic Reticulum Chaperone BiP
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HSPA5 protein, human
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Heat-Shock Proteins
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Hspa5 protein, mouse
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IL11 protein, human
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IL6 protein, human
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Interleukin-11
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Interleukin-6
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MicroRNAs
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STAT3 Transcription Factor
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STAT3 protein, human
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mirn199 microRNA, human
Supplementary concepts
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Pulmonary Arteriovenous Fistulas