Metoprolol Inhibits Profibrotic Remodeling of Epicardial Adipose Tissue in a Canine Model of Chronic Obstructive Sleep Apnea
Metoprolol Inhibits Profibrotic Remodeling of Epicardial Adipose Tissue in a Canine Model of Chronic Obstructive Sleep Apnea
复制标题
美托洛尔抑制慢性阻塞性睡眠呼吸暂停犬模型心外膜脂肪组织的促纤维化重塑
DOI：
10.1161/jaha.118.011155
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发表时间：
2019-02-05
影响因子：
5.4
通讯作者：
Li, Yue
中科院分区：
文献类型：
--
作者：
Dai, Hui;Yuan, Yue;Li, Yue
背景慢性阻塞性睡眠呼吸暂停（OSA）是否可促进心外膜脂肪组织（EAT）分泌促纤维化脂肪因子，从而促进心房纤维化，以及美托洛尔的潜在治疗作用尚不清楚。方法和结果采用反复夹闭气管导管，然后隔日再开放4 h，连续12周的方法建立慢性阻塞性睡眠呼吸暂停（OSA）犬模型。在美托洛尔治疗组中，每日给予琥珀酸美托洛尔，持续12周。观察EAT浸润及左房纤维化情况。检测EAT和缺氧3 T3 ‐L1脂肪细胞分泌的脂肪因子的表达。进一步分析缺氧3 T3-L1脂肪细胞来源的条件培养基诱导的心脏成纤维细胞胶原合成、转化生长因子-β1表达以及细胞分化和增殖的变化。慢性阻塞性睡眠呼吸暂停诱发EAT向左心房浸润。OSA增强EAT对邻近心房肌的促纤维化作用。此外，OSA诱导EAT分泌促纤维化细胞因子。我们还发现，缺氧诱导培养的脂肪细胞分泌脂肪因子，缺氧脂肪细胞的条件培养基增加胶原和转化生长因子-β1蛋白表达和心脏成纤维细胞的细胞增殖。更重要的是，美托洛尔通过抑制脂肪因子的分泌，减弱EAT的浸润，减轻EAT的促纤维化作用。美托洛尔还抑制脂肪细胞中缺氧诱导的脂肪因子分泌，从而阻断缺氧脂肪细胞来源的条件培养基诱导的心脏成纤维细胞纤维化反应。结论慢性OSA可通过刺激EAT分泌促纤维化脂肪因子，增强EAT对邻近心房肌的促纤维化作用，而美托洛尔可显著抑制EAT的促纤维化作用。这项研究为OSA诱发房颤的机制提供了新的见解，也为美托洛尔的保护作用提供了实验证据。
Background Whether chronic obstructive sleep apnea (OSA) could promote epicardial adipose tissue (EAT) secretion of profibrotic adipokines, and thereby contribute to atrial fibrosis, and the potential therapeutic effects of metoprolol remain unknown. Methods and Results A chronic OSA canine model was established by repeatedly clamping the endotracheal tube for and then reopening it for 4 hours every other day for 12 weeks. In a metoprolol treatment group, metoprolol succinate was administered daily for 12 weeks. The EAT infiltration and left atrial fibrosis were examined. The expressions of adipokines secreted by EAT and hypoxic 3T3‐L1 adipocytes were detected. The changes in collagen synthesis, transforming growth factor‐β1 expression, and cell differentiation and proliferation in cardiac fibroblasts induced by hypoxic 3T3‐L1 adipocyte‐derived conditioned medium were further analyzed. Chronic OSA induced infiltration of EAT into the left atrium. OSA enhanced the profibrotic effect of EAT on the adjacent atrial myocardium. Moreover, OSA induced profibrotic cytokine secretion from EAT. We also found that hypoxia induced adipokine secretion in cultured adipocytes, and the medium conditioned by the hypoxic adipocytes increased collagen and transforming growth factor‐β1 protein expression and cell proliferation of cardiac fibroblasts. More importantly, metoprolol attenuated infiltration of EAT and alleviated the profibrotic effect of EAT by inhibiting adipokine secretion. Metoprolol also inhibited hypoxia‐induced adipokine secretion in adipocytes and thereby blocked the hypoxic adipocyte–derived conditioned medium–induced fibrotic response of cardiac fibroblasts. Conclusions Chronic OSA enhanced the profibrotic effect of EAT on the neighboring atrial myocardium by stimulating the secretion of profibrotic adipokines from EAT, which was significantly attenuated by metoprolol. This study gives insights into mechanisms underlying OSA‐induced atrial fibrillation and also provides experimental evidence for the protective effects of metoprolol.