Serum from patients with severe heart failure downregulates eNOS and is proapoptotic: role of tumor necrosis factor-alpha.
Serum from patients with severe heart failure downregulates eNOS and is proapoptotic: role of tumor necrosis factor-alpha.
复制标题
严重心力衰竭患者的血清下调 eNOS 并促进细胞凋亡：肿瘤坏死因子-α 的作用。
作者：
L. Agnoletti;S. Curello;T. Bachetti;F. Malacarne;G. Gaia;L. Comini;M. Volterrani;P. Bonetti;G. Parrinello;M. Cadei;P. Grigolato;R. Ferrari
背景
细胞因子激活和内皮功能障碍是充血性心力衰竭（CHF）的典型现象。我们测试的假设，孵育人脐静脉内皮细胞与血清从CHF患者将下调内皮型一氧化氮合酶（eNOS），并诱导细胞凋亡。
方法和结果
我们研究了21例严重CHF患者。评估肿瘤坏死因子-α（TNF-α）水平和几个神经内分泌参数。通过Western Blot分析检测eNOS，通过光学显微镜和流式细胞术检测凋亡。我们观察到（1）eNOS下调（与健康受试者在24小时[P<0.05]和48小时[P<0.001]的差异），（2）典型的细胞凋亡的核形态学变化;和（3）碘化丙啶的高细胞凋亡率（在48小时从2.1+/-0.4%增加到11.3+/-1.2%;相对于健康受试者P<0.001）和膜联蛋白V。抗人TNF-α抗体不能完全抵消这些作用。eNOS表达下调与细胞凋亡呈显著正相关（r = -0.89; P<0.001）。
结论
严重CHF患者血清下调eNOS表达并增加细胞凋亡。高水平的TNF-α可能发挥作用，但它们不是唯一的因素。
BACKGROUND
Cytokine activation and endothelial dysfunction are typical phenomena of congestive heart failure (CHF). We tested the hypothesis that incubating human umbilical vein endothelial cells with serum from patients with CHF will downregulate endothelial constitutive nitric oxide synthase (eNOS) and induce apoptosis.
METHODS AND RESULTS
We studied 21 patients with severe CHF. Levels of tumor necrosis factor-alpha (TNF-alpha) and several neuroendocrine parameters were assessed. eNOS was measured by Western Blot analysis and apoptosis by optical microscopy and flow cytometry. We observed (1) eNOS downregulation (difference versus healthy subjects at 24 hours [P<0.05] and 48 hours [P<0.001]), (2) nuclear morphological changes typical of apoptosis; and (3) a high apoptotic rate with propidium iodide (increasing from 2.1+/-0.4% to 11.3+/-1.2% at 48 hours; P<0.001 versus healthy subjects) and annexin V. An anti-human TNF-alpha antibody did not completely counteract these effects. A strong correlation existed between eNOS downregulation and apoptosis (r = -0.89; P<0.001).
CONCLUSIONS
Serum from patients with severe CHF downregulates eNOS expression and increases apoptosis. High levels of TNF-alpha likely play a role, but they cannot be the only factor responsible.
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