Role of Adipose Tissue Endothelial ADAM17 in Age-Related Coronary Microvascular Dysfunction.
Role of Adipose Tissue Endothelial ADAM17 in Age-Related Coronary Microvascular Dysfunction.
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DOI：
10.1161/atvbaha.117.309430
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
Bagi Z
中科院分区：
文献类型：
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作者：
Dou H;Feher A;Davila AC;Romero MJ;Patel VS;Kamath VM;Gooz MB;Rudic RD;Lucas R;Fulton DJ;Weintraub NL;Bagi Z
解整合素和金属蛋白酶ADAM 17（TNF-α转化酶）调节可溶性TNF水平。我们检验了这样一个假设，即衰老诱导的脂肪组织（AT）表达的ADAM 17激活有助于肥胖患者远端冠状动脉微血管功能障碍（CMD）的发展。本文观察了10例年龄69± 11岁的右心耳和纵隔AT的冠状动脉（CA，~90 μm），BMI：30.2±5.6），接受了心内直视手术。CA和AT还研究了6个月和24个月的瘦和肥胖小鼠喂养正常或高脂肪饮食（HFD）。我们发现肥胖只在老年患者和老年HFD小鼠中引起内皮依赖性CA扩张受损。从老年肥胖小鼠移植AT，而不是从年轻或老年小鼠移植AT，增加血清细胞因子水平，包括TNF，并损害年轻受体小鼠CA扩张。在患者和小鼠中，肥胖伴随着与年龄相关的ADAM 17激活，这归因于血管内皮表达的ADAM 17。在一项AT动脉与CA串联的生物测定中，老年肥胖患者AT动脉中过量的ADAM 17-脱落TNF足以损害CA扩张。此外，我们发现，内皮细胞ADAM 17的活性增加是由减少与小窝蛋白-1的抑制性相互作用介导的，这是由于年龄相关的小窝蛋白-1在肥胖患者和小鼠中的表达下降或遗传缺失的小窝蛋白-1。目前的研究表明，衰老和肥胖协同降低Cav 1表达，增加血管内皮细胞ADAM 17活性和可溶性TNF释放的AT，这可能有助于远程CMD在老年肥胖患者的发展。
A disintegrin and metalloproteinase ADAM17 (TNF-α converting enzyme) regulates soluble TNF levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed ADAM17 contributes to the development of remote coronary microvascular dysfunction (CMD) in obesity. Coronary arterioles (CA,~90 μm) from right atrial appendages and mediastinal AT were examined in patients (age:69±11yrs.,BMI:30.2±5.6) who underwent open-heart surgery. CA and AT were also studied in 6-month and 24-month lean and obese mice fed a normal or high-fat diet (HFD). We found that obesity elicited impaired endothelium-dependent CA dilations only in older patients and in aged HFD mice. Transplantation of AT from aged obese, but not from young or aged mice increased serum cytokine levels, including TNF, and impaired CA dilation in the young recipient mice. In patients and mice obesity was accompanied by age-related activation of ADAM17, which was attributed to vascular endothelium-expressed ADAM17. Excess, ADAM17-shed TNF from AT arteries in older obese patients was sufficient to impair CA dilation in a bioassay in which the AT artery was serially connected to a CA. Moreover, we found that the increased activity of endothelial ADAM17 is mediated by a diminished inhibitory interaction with caveolin-1, owing to age-related decline in caveolin-1 expression in obese patients and mice or to genetic deletion of caveolin-1. The present study indicates that aging and obesity cooperatively reduce Cav1 expression, increase vascular endothelial ADAM17 activity and soluble TNF release in AT, which may contribute to the development of remote CMD in older obese patients.