Aortic dysfunction in metabolic syndrome mediated by perivascular adipose tissue TNFα- and NOX2-dependent pathway.
Aortic dysfunction in metabolic syndrome mediated by perivascular adipose tissue TNFα- and NOX2-dependent pathway.
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DOI：
10.1113/ep086818
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发表时间：
2018-04-01
影响因子：
2.7
通讯作者：
Chantler PD
中科院分区：
文献类型：
--
作者：
DeVallance E;Branyan KW;Lemaster K;Olfert IM;Smith DM;Pistilli EE;Frisbee JC;Chantler PD
血管周围脂肪组织（PVAT）被认为具有血管活性作用，但目前尚不清楚代谢综合征如何影响胸主动脉（t）PVAT以及随后对功能和结构主动脉僵硬度的影响。从16-17周龄瘦（LZR，n=16）和肥胖Zucker（OZR，n=16）大鼠中取出胸主动脉和tPVAT。OZR表现为主动脉内皮功能障碍（通过钢丝肌造影评估）和主动脉僵硬度增加（通过弹性模量评估）。OZR-tPVAT渗出物进一步加重了内皮功能障碍，减少了一氧化氮和内皮依赖性舒张（p<0.05）。此外，在共培养72小时后，OZR-tPVAT渗出物增加了MMP 9活性（p<0.05），并进一步增加了主动脉的弹性模量（p<0.05）。我们发现OZR-tPVAT引起的主动脉功能障碍是通过增加TNFα的产生和释放介导的（p<0.01），这依赖于tPVAT NADPH氧化酶2（NOX 2）活性。OZR-tPVAT ROS和随后的主动脉功能障碍可通过TNFα中和和/或抑制NOX 2来抑制。OZR-tPVAT还能降低20 S蛋白酶体活性位点的活性（p<0.05）和超氧化物歧化酶活性（p<0.01）。代谢综合征通过TNFα和NOX 2之间的相互作用引起tPVAT功能障碍，导致tPVAT介导的主动脉僵硬（通过激活主动脉ROS和MMP 9活性增加）。
Perivascular adipose tissue (PVAT) is recognized for its vaso-active effects, however it’s unclear how Metabolic Syndrome impact thoracic-aorta (t)PVAT and the subsequent effect on functional and structural aortic stiffness. Thoracic aorta and tPVAT were removed from 16–17 week old lean (LZR, n=16) and obese Zucker (OZR, n=16) rats. OZR presented with aortic endothelial dysfunction, assessed by wire-myography, and increased aortic stiffness, assessed by elastic modulus. OZR-tPVAT exudate further exacerbated the endothelial dysfunction reducing nitric oxide and endothelial dependent relaxation (p<0.05). Additionally, OZR-tPVAT exudate had increased MMP9 activity (p<0.05) and further increased elastic modulus of the aorta following 72-hours of coculture (p<0.05). We found the observed aortic dysfunction caused by OZR-tPVAT was mediated through increased production and release of TNFα (p<0.01), which was dependent on tPVAT NADPH-oxidase 2 (NOX2) activity. OZR-tPVAT ROS and subsequent aortic dysfunction was inhibited by TNFα neutralization and/ or inhibition of NOX2. Additionally, we found OZR-tPVAT had reduced activity of the 20S proteasome’s active sites (p<0.05) and reduced superoxide dismutase activity (p<0.01). Metabolic syndrome causes tPVAT dysfunction through interplay between TNFα and NOX2 leading to tPVAT mediated aortic stiffness by activation of aortic ROS and increased MMP9 activity.