Resveratrol protects against CIH-induced myocardial injury by targeting Nrf2 and blocking NLRP3 inflammasome activation.
白藜芦醇通过靶向 Nrf2 和阻断 NLRP3 炎症小体激活来保护 CIH 诱导的心肌损伤。
- 作者列表："Sun ZM","Guan P","Luo LF","Qin LY","Wang N","Zhao YS","Ji ES
:The prominent feature of obstructive sleep apnea (OSA) is chronic intermittent hypoxia (CIH). Given the strong antioxidant ability of resveratrol against oxidative stress, we evaluated the potential protective effects of resveratrol on myocardial injury induced by CIH. Twenty-four rats were divided into normal control group, CIH group, CIH plus resveratrol treated (CIH + Res) group, and resveratrol treated control (Res) group. We proved that CIH impaired cardiac structure and function with an increase in oxidative stress, endoplasmic reticulum (ER) stress and NOD-like receptors (NLRP3) inflammasome induction in heart, which was attenuated after resveratrol administration. NLRP3 inflammasome blockade by resveratrol appeared to be mediated by activating AMP-activated Protein Kinase (AMPK), which could restrain mTOR/TTP/NLRP3 mRNA signalling. Furthermore, resveratrol attenuated CIH-induced oxidative stress through elevation antioxidant molecules expression via NF-E2-related factor-2 (Nrf2). Moreover, AMPK may play a role in Nrf2/HO-1 signalling by resveratrol. These results expand our understanding of the myocardial protective mechanism of resveratrol during CIH and suggest that resveratrol treatment may be useful to counteract OSA-associated cardiac injury.
阻塞性睡眠呼吸暂停 (OSA) 的显著特征是慢性间歇性缺氧 (CIH)。鉴于白藜芦醇抗氧化应激的强抗氧化能力，我们评价了白藜芦醇对 CIH 诱导的心肌损伤的潜在保护作用。将 24 只大鼠分为正常对照组、 CIH 组、 CIH 加白藜芦醇治疗组 (CIH + Res) 和白藜芦醇对照组 (Res)。我们证明 CIH 损害了心脏结构和功能，增加了心脏的氧化应激、内质网 (ER) 应激和 NOD 样受体 (NLRP3) 炎症小体诱导, 白藜芦醇给药后减弱。白藜芦醇阻断 NLRP3 炎性体似乎是通过激活 AMP 激活的蛋白激酶 (AMPK) 介导的，AMPK 可以抑制 mTOR/TTP/NLRP3 mRNA 信号。此外，白藜芦醇通过 NF-E2-related 因子-2 (Nrf2) 提高抗氧化分子的表达来减弱 CIH 诱导的氧化应激。此外，AMPK 可能在白藜芦醇的 Nrf2/HO-1 信号传导中发挥作用。这些结果扩大了我们对 CIH 期间白藜芦醇心肌保护机制的理解，并提示白藜芦醇治疗可能有助于对抗 OSA 相关的心脏损伤。
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.
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.
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.