Interaction of IL-6 and TNF-α contributes to endothelial dysfunction in type 2 diabetic mouse hearts.
Interaction of IL-6 and TNF-α contributes to endothelial dysfunction in type 2 diabetic mouse hearts.
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DOI：
10.1371/journal.pone.0187189
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Park Y
中科院分区：
文献类型：
--
作者：
Lee J;Lee S;Zhang H;Hill MA;Zhang C;Park Y
炎症细胞因子，例如肿瘤坏死因子-α (TNF-α) 和白介素-6 (IL-6)，被单独认为是导致肥胖和 2 型糖尿病 (T2D) 内皮功能障碍的重要因素。然而，它们在冠状动脉内皮功能障碍中的相互作用尚不确定。因此，本研究旨在确定 TNF-α 和 IL-6 相互作用对实验性 T2D 冠状动脉内皮功能障碍的影响。研究使用野生型（WT）、糖尿病小鼠（db/db）、TNF 无效的 db/db 小鼠（dbTNF-/dbTNF-）以及用 IL-6 中和抗体（抗 IL-6）治疗的 db/db 小鼠。测定了分离和加压冠状动脉的内皮依赖性（乙酰胆碱 [ACh] 或管腔流诱导的剪切应力）和内皮非依赖性（硝普钠 [SNP]）血管舒张。利用定量 PCR、蛋白质印迹和免疫荧光染色进行机制研究。相对于WT，db/db小鼠和dbTNF-/dbTNF-的小动脉扩张对ACh和流量均减弱。与db/db小鼠相比，用抗IL-6治疗dbTNF-/dbTNF-和db/db小鼠改善了小动脉扩张。免疫荧光染色显示 IL-6 在冠状动脉内皮细胞内的定位。在 db/db 小鼠中，IL-6 的 mRNA 和蛋白表达以及超氧化物 (O2-) 的产生较高，但通过抗 IL-6 治疗而降低。此外，在 db/db 小鼠中，抗 IL-6 治疗抑制 TNF-α mRNA 和蛋白表达，以及 TNF-α 基因缺失导致 IL-6 mRNA 和蛋白表达减少，都支持 TNF-α 和 IL-6 之间的相互调节。 db/db 小鼠冠状动脉超氧化物歧化酶 2 (SOD2) 表达和 eNOS (p-eNOS/eNOS) 磷酸化水平较低，而 db/db+Anti-IL-6 和 dbTNF-/dbTNF- 小鼠则恢复。 TNF-α 和 IL-6 之间的相互作用会加剧氧化应激并降低 eNOS 磷酸化，从而导致 T2D 小鼠冠状动脉内皮功能障碍。
Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), are individually considered as important contributors to endothelial dysfunction in obesity and type 2 diabetes (T2D). However, their interactions in coronary arteriole endothelial dysfunction are uncertain. Therefore, this study aimed to determine the effects of TNF-α and IL-6 interactions on coronary endothelial dysfunction in experimental T2D. The studies used wild type (WT), diabetic mice (db/db), db/db null for TNF (dbTNF-/dbTNF-), and db/db mice treated with neutralizing antibody to IL-6 (anti-IL-6). Endothelium-dependent (acetylcholine [ACh], or luminal flow-induced shear stress) and endothelium-independent (sodium nitroprusside [SNP]) vasodilation of isolated and pressurized coronary arterioles were determined. Quantitative PCR, Western blot, and immunofluorescence staining were utilized for mechanistic studies. Relative to WT, arteriolar dilation to both ACh and flow was attenuated in db/db mice and dbTNF-/dbTNF-. Treatment of dbTNF-/dbTNF- and db/db mice with anti-IL-6 improved arteriolar dilation compared to db/db mice. Immunofluorescence staining illustrated localization of IL-6 within the endothelial cells of coronary arterioles. In db/db mice, mRNA and protein expression of IL-6 and superoxide (O2-) production were higher, but reduced by anti-IL-6 treatment. Also, in db/db mice, mRNA and protein expression of TNF-α suppressed by the anti-IL-6 treatment and the reduced expression of mRNA and protein expression of IL-6 by the genetic deletion of TNF-α both supported a reciprocal regulation between TNF-α and IL-6. Superoxide dismutase 2 (SOD2) expression and phosphorylation of eNOS (p-eNOS/eNOS) were lower in db/db mice coronary arterioles and were restored in db/db+Anti-IL-6 and dbTNF-/dbTNF- mice. The interactions between TNF-α and IL-6 exacerbate oxidative stress and reduce phosphorylation of eNOS, thereby contributing to coronary endothelial dysfunction in T2D mice.
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影响因子：
7.7
作者：
Duncan, BB;Schmidt, MI;Heiss, G
通讯作者：
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影响因子：
4.8
作者：
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作者：
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DOI：
10.1152/ajpheart.00271.2012
发表时间：
2012-09-01
影响因子：
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作者：
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DOI：
10.1152/ajpheart.01261.2007
发表时间：
2008-11-01
影响因子：
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作者：
Park, Yoonjung;Capobianco, Stefano;Zhang, Cuihua
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