Mutual Regulation of Epicardial Adipose Tissue and Myocardial Redox State by PPAR-γ/Adiponectin Signalling.
Mutual Regulation of Epicardial Adipose Tissue and Myocardial Redox State by PPAR-γ/Adiponectin Signalling.
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DOI：
10.1161/circresaha.115.307856
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发表时间：
2016-03-04
影响因子：
20.1
通讯作者：
Antoniades C
中科院分区：
文献类型：
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作者：
Antonopoulos AS;Margaritis M;Verheule S;Recalde A;Sanna F;Herdman L;Psarros C;Nasrallah H;Coutinho P;Akoumianakis I;Brewer AC;Sayeed R;Krasopoulos G;Petrou M;Tarun A;Tousoulis D;Shah AM;Casadei B;Channon KM;Antoniades C
补充数字内容可在文本中找到。脂联素在实验模型中具有抗炎作用，但其在人类心肌氧化还原状态调节中的作用尚不清楚。虽然脂联素可以从心外膜脂肪组织（EpAT）中释放出来，但它是否对人心肌有旁分泌作用尚不清楚。探讨epat源性脂联素与心肌氧化还原状态的交互作用。对306例冠状动脉搭桥术患者进行EpAT和心房心肌检测。增加ADIPOQ表达（编码脂联素）的功能性遗传多态性导致心肌烟酰胺腺嘌呤二核苷酸磷酸氧化酶衍生的O2−减少，而EpAT中循环脂联素和ADIPOQ表达与心肌O2−升高相关。在人心房组织中，我们证明了脂联素通过阻止AMP激酶介导的Rac1和p47phox从细胞质到膜的易位来抑制心肌烟酰胺腺嘌呤二核苷酸磷酸氧化酶的活性。诱导H9C2心肌细胞产生O2导致一种可转移因子的释放，该因子能够诱导共培养EpAT中过氧化物酶体增殖物激活受体-γ介导的ADIPOQ表达上调。利用NOX2转基因小鼠和猪心房快速起搏模型，我们发现心脏释放的氧化产物（如4-羟基壬烯醛）可触发EpAT中过氧化物酶体增殖物激活受体-γ介导的ADIPOQ上调。我们首次在人体中证明脂联素通过内分泌或旁分泌作用直接降低心肌烟酰胺腺嘌呤二核苷酸磷酸氧化酶活性。EpAT中的脂联素表达受心脏释放的氧化产物的旁分泌作用控制。这些作用构成了心脏对心肌氧化应激的一种新的防御机制。
Supplemental Digital Content is available in the text. Adiponectin has anti-inflammatory effects in experimental models, but its role in the regulation of myocardial redox state in humans is unknown. Although adiponectin is released from epicardial adipose tissue (EpAT), it is unclear whether it exerts any paracrine effects on the human myocardium. To explore the cross talk between EpAT-derived adiponectin and myocardial redox state in the human heart. EpAT and atrial myocardium were obtained from 306 patients undergoing coronary artery bypass grafting. Functional genetic polymorphisms that increase ADIPOQ expression (encoding adiponectin) led to reduced myocardial nicotinamide adenine dinucleotide phosphate oxidase–derived O2−, whereas circulating adiponectin and ADIPOQ expression in EpAT were associated with elevated myocardial O2−. In human atrial tissue, we demonstrated that adiponectin suppresses myocardial nicotinamide adenine dinucleotide phosphate oxidase activity, by preventing AMP kinase–mediated translocation of Rac1 and p47phox from the cytosol to the membranes. Induction of O2− production in H9C2 cardiac myocytes led to the release of a transferable factor able to induce peroxisome proliferator-activated receptor-γ–mediated upregulation of ADIPOQ expression in cocultured EpAT. Using a NOX2 transgenic mouse and a pig model of rapid atrial pacing, we found that oxidation products (such as 4-hydroxynonenal) released from the heart trigger peroxisome proliferator-activated receptor-γ–mediated upregulation of ADIPOQ in EpAT. We demonstrate for the first time in humans that adiponectin directly decreases myocardial nicotinamide adenine dinucleotide phosphate oxidase activity via endocrine or paracrine effects. Adiponectin expression in EpAT is controlled by paracrine effects of oxidation products released from the heart. These effects constitute a novel defense mechanism of the heart against myocardial oxidative stress.