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

MiRNA 介导的心脏保护因子的抑制作为一种新的机制,通过睡眠呼吸障碍加剧 MI 后重塑。

  • 影响因子:8.96
  • DOI:10.1161/CIRCRESAHA.119.315067
  • 作者列表:"Du Y","Wang X","Li L","Hao W","Zhang H","Li Y","Qin Y","Nie S","Christopher TA","Lopez BL","Lau WB","Wang Y","Ma XL","Wei Y
  • 发表时间:2020-01-17
Abstract

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.

摘要

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 不同时期的 CIH 暴露是否会加剧 MI 后心力衰竭,并确定 CIH 加剧 MI 后重构的潜在机制。 方法和结果: 成年雄性小鼠接受心肌梗死 (4 周),有无 CIH (4 或 8 周)。MI 前 CIH (CIH + MI) 对 MI 后重塑无显著影响。然而,双重 CIH 暴露 (CIH + MI + CIH) 或仅在 MI 期间的 CIH (MI + CIH) 显著加剧了病理重塑并降低了生存率。机制上,CIH 激活了 TGF-β (肿瘤生长因子-β)/Smad (果蝇蛋白 MAD 和 C 的同系物)。线虫蛋白 SMA) 信号和增强心脏上皮向间质转化,显著增加 MI 后心脏纤维化。转录组分析发现,在 15 个基因中显著下调 (MI + CIH vs.MI),Ctrp9 (一种新型心脏保护性 cardiokine) 是最显著抑制的基因之一。实时聚合酶链反应/Western 分析证实,MI + CIH 小鼠心肌细胞 CTRP9 表达显著降低。RNA 测序、实时聚合酶链反应和双荧光素酶报告基因检测发现 microRNA-214-3p 是一种新型的靶向 miRNA 的 Ctrp9。其上调负责 MI + CIH 中 Ctrp9 基因的抑制。最后,AAV9 (腺相关病毒 9) 介导的心脏特异性 CTRP9 过表达或 rCTRP9 (重组 CTRP9) 给药抑制了 TGF-β/Smad 和 Wnt/β-catenin 通路, 减轻 MI + CIH 动物的间质纤维化,改善心功能,提高生存率。 结论: 本研究首次证明 MI + CIH 上调 miR-214-3p,抑制心脏 CTRP9 (C1q 肿瘤坏死因子相关蛋白-9) 表达,加剧心脏重构, 提示 CTRP9 可能是治疗阻塞性睡眠呼吸暂停低通气综合征心肌梗死患者病理性重塑的新靶点。

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影响因子:5.5150
发表时间:2020-01-29
来源期刊:Aging
DOI:10.18632/aging.102729
作者列表:["Chen Q","Lin G","Huang J","Chen L","Liu Y","Huang J","Zhang S","Lin Q"]

METHODS:OBJECTIVE:The functions and molecular regulatory mechanisms of miR-193a-3p in cardiac injury induced by obstructive sleep apnea (OSA) are poorly understood. This study aimed to explore the role of miR-193a-3p in intermittent hypoxia(IH)-induced human umbilical vein endothelial cells (HUVECs) injury. RESULTS:In this study, we found that IH significantly decreased viability but enhanced cell apoptosis. Concurrently, the miR-193a-3p expression level was increased in HUVECs after IH. Subsequent experiments showed that IH-induced injury was ameliorated through miR-193a-3p silence. Fas apoptotic inhibitory molecule 2 (FAIM2) was predicted by bioinformatics analysis and further identified as a direct target gene of miR-193a-3p. Interestingly, the effect of miR-193a-3p inhibition under IH could be reversed by down-regulating FAIM2 expression. CONCLUSION:In conclusion, our study first revealed that miR-193a-3p inhibition could protect HUVECs against intermittent hypoxia-induced damage by negatively regulating FAIM2. These findings could advance our understanding of the underlying mechanisms for OSA-related cardiac injury. METHODS:We exposed HUVECs to IH condition; the expression levels of miR-193a-3p were detected by RT-qPCR. Cell viability, and the expressions of apoptosis-associated proteins were examined via CCK-8, and western blotting, respectively. Target genes of miR-193a-3p were confirmed by dual-luciferase reporter assay.

翻译标题与摘要 下载文献
影响因子:8.96
发表时间:2020-01-17
来源期刊:Circulation research
DOI:10.1161/CIRCRESAHA.119.315067
作者列表:["Du Y","Wang X","Li L","Hao W","Zhang H","Li Y","Qin Y","Nie S","Christopher TA","Lopez BL","Lau WB","Wang Y","Ma XL","Wei Y"]

METHODS: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.

翻译标题与摘要 下载文献
影响因子:2.83
发表时间:2020-01-15
DOI:10.5664/jcsm.8124
作者列表:["Mendelson M","Inami T","Lyons O","Alshaer H","Marzolini S","Oh P","Bradley TD"]

METHODS:STUDY OBJECTIVES:Sleep apnea (SA) is prevalent among patients with coronary artery disease (CAD) and increases cardiovascular risk. A previous study showed that 1 month of cardiac rehabilitation (CR) reduced severity of SA in patients with CAD by reducing fluid accumulation in the legs during the day and the amount of fluid shifting rostrally into the neck overnight. The aim of this study was to evaluate whether CR will lead to longer-term attenuation of SA in patients with CAD. METHODS:Fifteen patients with CAD and SA who had participated in a 1-month randomized trial of the effects of exercise training on SA were followed up until they completed 6 months of CR (age: 65 ± 10 years; body mass index: 27.0 ± 3.9 kg/m²; apnea-hypopnea index [AHI]: 39.0 ± 16.7). The AHI was evaluated at baseline by polysomnography and then at 6 months by portable monitoring at home. Cardiorespiratory fitness (VO2peak) was evaluated via a graded cardiopulmonary exercise test at baseline and 6 months later. The 6-month CR program included once weekly, 90-minute, in-facility exercise sessions, and 4 days per week at-home exercise sessions. RESULTS:After 6 months of CR, there was a 54% reduction in the AHI (30.5 ± 15.2 to 14.1 ± 7.5, P < .001). Body mass index remained unchanged, but VO2peak increased by 27% (20.0 ± 6.1 to 26.0 ± 8.9 mL/kg/min, P = .04). CONCLUSIONS:Participation in CR is associated with a significant long-term decrease in the severity of SA. This finding suggests that attenuation of SA by exercise could be a mechanism underlying reduced mortality following participation in CR in patients with CAD and SA. CLINICAL TRIAL REGISTRATION:This study is registered at www.controlled-trials.com with identifier number ISRCTN50108373.

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