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miRNA‐Mediated Suppression of a Cardioprotective Cardiokine as a Novel Mechanism Exacerbating Post‐MI Remodeling by Sleep Breathing Disorders
Author(s) -
Du Yunhui,
Wei Yongxiang,
Christopher Theodore,
Lopez Bernard,
Ma Xinliang,
Wang Yajing
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00725
Subject(s) - medicine , ventricular remodeling , downregulation and upregulation , myocardial infarction , fibrosis , cardiac fibrosis , wnt signaling pathway , sleep apnea , smad , endocrinology , cardiology , signal transduction , biology , transforming growth factor , microbiology and biotechnology , gene , biochemistry
Background Obstructive sleep apnea (OSA), a sleep breathing disorder in which chronic intermittent hypoxia (CIH) is the primary pathology, is associated with multiple cardiovascular diseases. However, whether and how CIH may affect cardiac remodeling following myocardial infarction (MI) remains unknown. Methods and Results Adult male mice were subjected to MI (4 weeks) with and without CIH (4 or 8 weeks). CIH prior to MI (CIH+MI) had no significant effect upon post‐MI remodeling. However, double CIH exposure (CIH+MI+CIH) or CIH only during the MI period (MI+CIH) significantly exacerbated pathologic remodeling and reduced survival rate. Mechanistically, CIH activated TGF‐b/Smad signaling and enhanced cardiac epithelial to mesenchymal transition, markedly increasing post‐MI cardiac fibrosis. Transcriptome analysis revealed that, among 15 genes significantly downregulated (MI+CIH versus MI), Ctrp9 (a novel cardioprotective cardiokine) was one of the most significantly inhibited genes. Rt‐PCR/Western analysis confirmed that cardiomyocyte Ctrp9 expression was significantly reduced in MI+CIH mice. RNA‐seq, Rt‐PCR, and dual‐luciferase reporter assays identified that miR‐214‐3p is a novel Ctrp9 targeting miRNA. Its upregulation is responsible for Ctrp9 gene suppression in MI+CIH. Finally, AAV9‐mediated cardiac‐specific Ctrp9 overexpression or rCTRP9 administration inhibited TGF‐b/Smad and Wnt/β‐catenin pathways, attenuated interstitial fibrosis, improved cardiac function, and enhanced survival rate in MI+CIH animals. Conclusions This study provides the first evidence that MI+CIH upregulates miR‐214‐3p, suppresses cardiac CTRP9 expression, and exacerbates cardiac remodeling, suggesting that CTRP9 may be a novel therapeutic target against pathologic remodeling in MI patients with OSA.