Inhibition of TNF in the brain reverses alterations in RAS components and attenuates angiotensin II-induced hypertension.
Inhibition of TNF in the brain reverses alterations in RAS components and attenuates angiotensin II-induced hypertension.
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TNF在大脑中的抑制会逆转RAS成分的改变，并减弱血管紧张素II诱导的高血压。
DOI：
10.1371/journal.pone.0063847
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Francis J
中科院分区：
文献类型：
--
作者：
Sriramula S;Cardinale JP;Francis J
脑肾素-血管紧张素系统（RAS）成分的功能障碍与高血压的发生有关。我们之前的研究表明，血管紧张素（Ang） ii诱导的高血压是由脑心血管调节中心（如室旁核（PVN））中促炎细胞因子（PIC）的增加介导的，包括肿瘤坏死因子（TNF）。目前，我们验证了中枢TNF阻断可防止脑RAS成分失调并减轻Ang ii诱导的高血压的假设。雄性Sprague-Dawley大鼠植入无线电遥测发射器测量平均动脉压（MAP），并在脑室（ICV）内注射依那西普（10µg/kg/天），同时/不同时皮下注射Ang II (200 ng/kg/min) 4周。慢性输注Ang II导致MAP和心肌肥厚显著增加，依那西普抑制脑TNF减轻了这一现象。依那西普治疗也减弱了Ang ii诱导的PIC升高和PVN中IL-10表达的降低。此外，Ang II输注增加了PVN内促高血压RAS成分（ACE和AT1R）的表达，同时降低了抗高血压RAS成分（ACE2、Mas和AT2受体）的表达。ICV依那西普治疗逆转了这些变化。通过增加PVN中NAD(P)H氧化酶活性和超氧化物的产生，Ang ii输注与氧化应激增加有关，这可以通过抑制TNF来阻止。此外，脑靶向TNF阻断显著降低了Ang ii诱导的PVN中NOX-2和NOX-4 mRNA和蛋白的表达。这些发现表明，脑内慢性TNF阻断通过恢复促高血压和抗高血压RAS轴之间的平衡以及抑制PVN中的PIC和氧化应激基因和蛋白质，保护大鼠免受Ang ii依赖性高血压和心脏肥厚的影响。
Dysfunction of brain renin-angiotensin system (RAS) components is implicated in the development of hypertension. We previously showed that angiotensin (Ang) II-induced hypertension is mediated by increased production of proinflammatory cytokines (PIC), including tumor necrosis factor (TNF), in brain cardiovascular regulatory centers such as the paraventricular nucleus (PVN). Presently, we tested the hypothesis that central TNF blockade prevents dysregulation of brain RAS components and attenuates Ang II-induced hypertension. Male Sprague-Dawley rats were implanted with radio-telemetry transmitters to measure mean arterial pressure (MAP) and subjected to intracerebroventricular (ICV) infusion of etanercept (10 µg/kg/day) with/without concurrent subcutaneous 4-week Ang II (200 ng/kg/min) infusion. Chronic Ang II infusion resulted in a significant increase in MAP and cardiac hypertrophy, which was attenuated by inhibition of brain TNF with etanercept. Etanercept treatment also attenuated Ang II-induced increases in PIC and decreases in IL-10 expression in the PVN. Additionally, Ang II infusion increased expression of pro-hypertensive RAS components (ACE and AT1R), while decreasing anti-hypertensive RAS components (ACE2, Mas, and AT2 receptors), within the PVN. ICV etanercept treatment reversed these changes. Ang II-infusion was associated with increased oxidative stress as indicated by increased NAD(P)H oxidase activity and super oxide production in the PVN, which was prevented by inhibition of TNF. Moreover, brain targeted TNF blockade significantly reduced Ang II-induced NOX-2 and NOX-4 mRNA and protein expression in the PVN. These findings suggest that chronic TNF blockade in the brain protects rats against Ang II-dependent hypertension and cardiac hypertrophy by restoring the balance between pro- and anti-hypertensive RAS axes and inhibiting PIC and oxidative stress genes and proteins in the PVN.
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