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Circ Res. 2019 Nov 7. doi: 10.1161/CIRCRESAHA.119.315067. [Epub ahead of print]

miRNA-Mediated Suppression of a Cardioprotective Cardiokine as a Novel Mechanism Exacerbating Post-MI Remodeling by Sleep Breathing Disorders.

Author information

1
Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University.
2
Emergency and Critical Care Center, Beijing Anzhen Hospital, Capital Medical University.
3
Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University.
4
Beijing Institute of Heart Lung and Blood Vessel Disease,, Beijing Anzhen Hospital, Capital Medical University.
5
Beijing Key Laboratory of Upper Airway Dysfunction-Related Cardiovascular Diseases, Beijing Anzhen Hospital, Capital Medical University.
6
Emergency Medicine, Thomas Jefferson University.
7
Otolaryngology Head and Neck Surgery, Beijing Anzhen Hospital, Capital Medical University.

Abstract

Rationale: 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. Objective: To determine whether CIH exposure at different periods of MI may exacerbate post-MI heart failure and to identify the mechanisms underlying CIH-exacerbated post-MI remodeling. 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-beta/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-beta/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.

KEYWORDS:

Cardiokine; sleep breathing disorders

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