Tumor Necrosis Factor - Alpha Is Essential for Angiotensin II-Induced Ventricular Remodeling: Role for Oxidative Stress.
Tumor Necrosis Factor - Alpha Is Essential for Angiotensin II-Induced Ventricular Remodeling: Role for Oxidative Stress.
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DOI：
10.1371/journal.pone.0138372
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Francis J
中科院分区：
文献类型：
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作者：
Sriramula S;Francis J
血管紧张素II （Ang II）和肿瘤坏死因子(TNF)-α之间的功能性串扰已被证明可引起高血压患者不良的左心室重构和肥厚。我们实验室之前的研究表明，缺乏TNF-α (TNF-α-/-)的小鼠对Ang II的高血压反应减弱；然而，所涉及的信号机制尚不清楚。在这项研究中，我们研究了参与Ang II和TNF-α相互作用的信号通路。慢性输注（1μg/kg/min, 14 d）可显著提高野生型（WT）小鼠心肌I型胶原、III型胶原、CTGF和TGF-β mRNA和蛋白的表达，而TNF-α-/-小鼠则降低上述变化。与输注Ang II的WT小鼠相比，TNF-α-/-小鼠的心肌血管周围和间质纤维化减少。在WT小鼠中，Ang II输注增加了活性氧的形成和NADPH氧化酶亚基的表达，表明氧化应激增加，但在TNF-α-/-小鼠中没有。此外，以依那西普（8mg /kg，每3天）治疗2周，可使angii诱导的WT小鼠高血压（133±4 vs 154±3 mmHg, p<0.05）和心脏肥厚（心重与体重比，4.8±0.2 vs 5.6±0.3,p<0.05）减弱。此外，在TNF-α-/-小鼠和依那西普治疗的小鼠中，Ang ii诱导的NF-κ b、p38 MAPK和JNK的活化均降低。综上所述，这些发现表明TNF-α参与了Ang ii诱导的高血压和不良心脏重构，这些影响与氧化应激依赖性MAPK/TGF-β/NF-κB通路的变化有关。这些结果可能为探讨Ang II和TNF-α相互作用的机制提供新的见解。
The functional crosstalk between angiotensin II (Ang II) and tumor necrosis factor (TNF)-α has been shown to cause adverse left ventricular remodeling and hypertrophy in hypertension. Previous studies from our lab showed that mice lacking TNF-α (TNF-α-/-) have attenuated hypertensive response to Ang II; however, the signaling mechanisms involved are not known. In this study, we investigated the signaling pathways involved in the Ang II and TNF-α interaction. Chronic Ang II infusion (1μg/kg/min, 14 days) significantly increased cardiac collagen I, collagen III, CTGF and TGF-β mRNA and protein expression in wild-type (WT) mice, whereas these changes were decreased in TNF-α-/- mice. TNF-α-/- mice with Ang II infusion showed reduced myocardial perivascular and interstitial fibrosis compared to WT mice with Ang II infusion. In WT mice, Ang II infusion increased reactive oxygen species formation and the expression of NADPH oxidase subunits, indicating increased oxidative stress, but not in TNF-α-/- mice. In addition, treatment with etanercept (8 mg/kg, every 3 days) for two weeks blunted the Ang II-induced hypertension (133±4 vs 154±3 mmHg, p<0.05) and cardiac hypertrophy (heart weight to body weight ratio, 4.8±0.2 vs 5.6±0.3, p<0.05) in WT mice. Furthermore, Ang II-induced activation of NF-κB, p38 MAPK, and JNK were reduced in both TNF-α-/- mice and mice treated with etanercept. Together, these findings indicate that TNF-α contributes to Ang II-induced hypertension and adverse cardiac remodeling, and that these effects are associated with changes in the oxidative stress dependent MAPK/TGF-β/NF-κB pathway. These results may provide new insight into the mechanisms of Ang II and TNF-α interaction.