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-β (tumor growth factor-β)/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-β/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 (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.

中文翻译：

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miRNA介导的心脏保护性心肌因子抑制作为一种新型机制，可加剧睡眠呼吸障碍引起的MI后重塑。

理由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系统疾病，与多种心血管疾病有关。但是，CIH是否以及如何影响心肌梗死（MI）后的心脏重塑仍是未知的。目的确定在不同心梗期暴露于CIH是否会加重心梗后心力衰竭，并确定CIH加重心梗后重塑的潜在机制。方法和结果成年雄性小鼠在有或没有CIH的情况下（4或8周）接受MI（4周）治疗。MI之前的CIH（CIH + MI）对MI后的重塑没有显着影响。但是，两次CIH暴露（CIH + MI + CIH）或仅在MI期（MI + CIH）期间的CIH会严重加剧病理重塑并降低生存率。机械上，CIH激活了TGF-β（肿瘤生长因子-β）/ Smad（果蝇蛋白MAD和秀丽隐杆线虫蛋白SMA的同源物）信号传导，并增强了心脏上皮到间质的转化，显着增加了MI后心脏纤维化。转录组分析显示，在15个被显着下调的基因（MI + CIH与MI）中，Ctrp9（一种新型的心脏保护性心肌因子）是抑制最严重的基因之一。实时聚合酶链反应/ Western分析证实，MI + CIH小鼠的心肌CTRP9表达明显降低。RNA测序，实时聚合酶链反应和双萤光素酶报告基因检测法确定microRNA-214-3p是靶向miRNA的新型Ctrp9。它的上调是MI + CIH中Ctrp9基因抑制的原因。最后，AAV9（腺伴随病毒9）介导的心脏特异性CTRP9过表达或rCTRP9（重组CTRP9）给药可抑制TGF-β/ Smad和Wnt /β-catenin途径，减轻间质纤维化，改善心脏功能，并提高MI的生存率+ CIH动物。结论这项研究提供了第一个证据，MI + CIH上调miR-214-3p，抑制心脏CTRP9（C1q肿瘤坏死因子相关蛋白9）的表达，并加重心脏重塑，提示CTRP9可能是针对病理学的新型治疗靶点。梗阻性睡眠呼吸暂停低通气综合征的心肌梗死患者重塑。并提高了MI + CIH动物的存活率。结论这项研究提供了第一个证据，MI + CIH上调miR-214-3p，抑制心脏CTRP9（C1q肿瘤坏死因子相关蛋白9）的表达，并加重心脏重塑，提示CTRP9可能是针对病理学的新型治疗靶点。梗阻性睡眠呼吸暂停低通气综合征的心肌梗死患者重塑。并提高了MI + CIH动物的存活率。结论这项研究提供了第一个证据，MI + CIH上调miR-214-3p，抑制心脏CTRP9（C1q肿瘤坏死因子相关蛋白9）的表达，并加重心脏重塑，提示CTRP9可能是针对病理学的新型治疗靶点。梗阻性睡眠呼吸暂停低通气综合征的心肌梗死患者重塑。