Enhanced NF-κB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes.
Enhanced NF-κB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes.
复制标题
增强的NF-κB活性通过2型糖尿病中的PARP-1-，SP-1-和COX-2依赖性机制损害了血管功能。
DOI：
10.2337/db12-1374
复制
发表时间：
2013-06
期刊：
影响因子：
7.7
通讯作者：
Matrougui K
中科院分区：
文献类型：
--
作者：
Kassan M;Choi SK;Galán M;Bishop A;Umezawa K;Trebak M;Belmadani S;Matrougui K
2型糖尿病（T2D）与血管功能障碍有关。我们假设核因子-κB （NF-κB）信号的增加与T2D的血管功能障碍有关。我们用两种NF-κB抑制剂（6 mg/kg dehydroxymethyllepoxyquinomicin，每周2次）和500 μg/kg/天IKK-NBD肽)治疗2型糖尿病（db - /db -）和对照组（db - /db+）小鼠，疗程4周。与对照组相比，压力诱导的肌张力明显增强，而内皮依赖性舒张（EDR）在糖尿病小鼠的小冠状动脉和肠系膜抵抗动脉中受损。有趣的是，用NF-κB抑制剂治疗的糖尿病小鼠显著降低了肌原性张力增强，改善了EDR。重要的是，与db - /db -小鼠相比，db - /db - p50NF-κB - / -和db - /db - PARP-1 - / -双敲除小鼠的血管功能也得到了恢复。此外，使用p65NF-κB短发夹RNA慢病毒在db - /db -小鼠动脉急性体外下调NF-κB - p65也能改善血管功能。抑制NF-κB不影响血糖水平和体重。Sp-1和eNOS磷酸化的RNA水平降低，而p65NF-κB磷酸化、cleaved poly（adp -核糖）聚合酶(PARP)-1和环氧化酶(COX)-2的表达升高，在NF-κB抑制后，db - /db - p50NF-κB - - / -和db - /db - PARP-1 - / -小鼠的动脉中恢复。在目前的研究中，我们提供的证据表明，在雄性2型糖尿病小鼠中，NF-κ b活性增强通过PARP-1 -、Sp-1 -和cox -2依赖机制损害血管功能。因此，NF-κB可能是克服糖尿病诱导的血管功能障碍的潜在靶点。
Type 2 diabetes (T2D) is associated with vascular dysfunction. We hypothesized that increased nuclear factor-κB (NF-κB) signaling contributes to vascular dysfunction in T2D. We treated type 2 diabetic (db−/db−) and control (db−/db+) mice with two NF-κB inhibitors (6 mg/kg dehydroxymethylepoxyquinomicin twice a week and 500 μg/kg/day IKK-NBD peptide) for 4 weeks. Pressure-induced myogenic tone was significantly potentiated, while endothelium-dependent relaxation (EDR) was impaired in small coronary arterioles and mesenteric resistance artery from diabetic mice compared with controls. Interestingly, diabetic mice treated with NF-κB inhibitors had significantly reduced myogenic tone potentiation and improved EDR. Importantly, vascular function was also rescued in db−/db−p50NF-κB−/− and db−/db−PARP-1−/− double knockout mice compared with db−/db− mice. Additionally, the acute in vitro downregulation of NF-κB–p65 using p65NF-κB short hairpin RNA lentivirus in arteries from db−/db− mice also improved vascular function. The NF-κB inhibition did not affect blood glucose level or body weight. The RNA levels for Sp-1 and eNOS phosphorylation were decreased, while p65NF-κB phosphorylation, cleaved poly(ADP-ribose) polymerase (PARP)-1, and cyclooxygenase (COX)-2 expression were increased in arteries from diabetic mice, which were restored after NF-κB inhibition and in db−/db−p50NF-κB−/− and db−/db−PARP-1−/− mice. In the current study, we provided evidence that enhanced NF-κB activity impairs vascular function by PARP-1–, Sp-1–, and COX-2–dependent mechanisms in male type 2 diabetic mice. Therefore, NF-κB could be a potential target to overcome diabetes-induced vascular dysfunction.
登录
查看更多内容
影响因子：
3.1
作者：
Kumar S;Sun X;Wiseman DA;Tian J;Umapathy NS;Verin AD;Black SM
通讯作者：
Black SM
影响因子：
--
作者：
Crofford, LJ;Tan, B;Hla, T
通讯作者：
Hla, T
影响因子：
8.8
作者：
通讯作者：
--
DOI：
10.4049/jimmunol.1001857
发表时间：
2010-10-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Benjamin JT;Carver BJ;Plosa EJ;Yamamoto Y;Miller JD;Liu JH;van der Meer R;Blackwell TS;Prince LS
通讯作者：
Prince LS
影响因子：
15.9
作者：
Harrison, DG
通讯作者：
Harrison, DG