miRNA-Mediated Suppression of a Cardioprotective Cardiokine as a Novel Mechanism Exacerbating Post-MI Remodeling by Sleep Breathing Disorders
miRNA-Mediated Suppression of a Cardioprotective Cardiokine as a Novel Mechanism Exacerbating Post-MI Remodeling by Sleep Breathing Disorders
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miRNA 介导的心脏保护性心肌因子抑制作为一种新机制，通过睡眠呼吸障碍加剧 MI 后重塑
DOI：
10.1161/circresaha.119.315067
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发表时间：
2020-01-17
影响因子：
20.1
通讯作者：
Wei, Yongxiang
中科院分区：
文献类型：
--
作者：
Du, Yunhui;Wang, Xiao;Wei, Yongxiang
基本原理：阻塞性睡眠呼吸暂停低通气综合征是一种以慢性间歇性缺氧（CIH）为主要病理的睡眠呼吸障碍，与多种心血管疾病相关。然而，CIH是否以及如何影响心肌梗死（MI）后的心脏重构仍不清楚。目的：确定MI不同时期CIH暴露是否可能加重MI后心力衰竭，并确定CIH加重MI后重塑的潜在机制。方法和结果：成年雄性小鼠进行MI（4周）与和不CIH（4或8周）。MI前CIH（CIH+MI）对MI后重构无显著影响。然而，两次CIH暴露（CIH+MI+CIH）或仅在MI期间CIH（MI+CIH）显著加重病理性重塑并降低生存率。从机制上讲，CIH激活了TGF-β（肿瘤生长因子-β）/Smad（果蝇蛋白MAD和C. elegans蛋白SMA）信号传导并增强心脏上皮向间充质转化，显著增加MI后心脏纤维化。转录组分析显示，在15个显著下调的基因（MI+CIH vs MI）中，Ctrp 9（一种新的心脏保护性心脏因子）是最显著抑制的基因之一。实时聚合酶链反应/Western分析证实，心肌细胞CTRP 9的表达在MI+CIH小鼠中显著降低。RNA测序、实时聚合酶链反应和双荧光素酶报告基因分析确定microRNA-214- 3 p是一种新型的Ctrp 9靶向miRNA。其上调是MI+CIH中Ctrp 9基因抑制的原因。最后，在MI+CIH动物中，AAV 9（腺相关病毒9）介导的心脏特异性CTRP 9过表达或rCTRP 9（重组CTRP 9）施用抑制TGF-β/Smad和Wnt/β-连环蛋白途径，减弱间质纤维化，改善心脏功能，并提高存活率。结论：本研究首次提供了MI+CIH上调miR-214- 3 p、抑制心脏CTRP 9（C1 q肿瘤坏死因子相关蛋白-9）表达并加剧心脏重构的证据，表明CTRP 9可能是MI伴阻塞性睡眠呼吸暂停低通气综合征患者病理性重构的新治疗靶点。
Rationale: Obstructive sleep apnea-hypopnea syndrome, 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 before MI (CIH+MI) had no significant effect on post-MI remodeling. However, double CIH exposure (CIH+MI+CIH) or CIH only during the MI period (MI+CIH) significantly exacerbated pathological remodeling and reduced survival rate. Mechanistically, CIH activated TGF-beta (tumor growth factor-beta)/Smad (homologs of both the Drosophila protein MAD and the C. elegans protein SMA) 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. Real-time polymerase chain reaction/Western analysis confirmed that cardiomyocyte CTRP9 expression was significantly reduced in MI+CIH mice. RNA-sequencing, real-time polymerase chain reaction, and dual-luciferase reporter assays identified that microRNA-214-3p is a novel Ctrp9 targeting miRNA. Its upregulation is responsible for Ctrp9 gene suppression in MI+CIH. Finally, AAV9 (adeno-associated virus 9)-mediated cardiac-specific CTRP9 overexpression or rCTRP9 (recombinated CTRP9) administration inhibited TGF-beta/Smad and Wnt/beta-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 (C1q tumor necrosis factor-related protein-9) expression, and exacerbates cardiac remodeling, suggesting that CTRP9 may be a novel therapeutic target against pathological remodeling in MI patients with obstructive sleep apnea-hypopnea syndrome.