Peripherally or centrally administered TNF-α elicits a prolonged sympathetically mediated pressor response, but the underlying molecular mechanisms are unknown. Activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in cardiovascular regions of the brain has recently been recognized as a key mediator of sympathetic excitation, and ERK1/2 signaling is induced by activation of epidermal growth factor receptor (EGFR) tyrosine kinase activity. The present study examined the role of EGFR and ERK1/2 signaling in the sympathetic response to TNF-α. In urethane-anesthetized rats, intracarotid artery injection of TNF-α increased phosphorylation of EGFR and ERK1/2 in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN), upregulated the gene expression of excitatory mediators in SFO and PVN, and increased blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA). A continuous intracerebroventricular infusion of the selective EGFR tyrosine kinase inhibitor AG1478 or the ERK1/2 inhibitor PD98059 significantly attenuated these responses. Bilateral PVN microinjections of TNF-α also increased phosphorylated ERK1/2 and the gene expression of excitatory mediators in PVN, along with increases in BP, HR and RSNA, and these responses were substantially reduced by prior bilateral PVN microinjections of AG1478. These results identify activation of EGFR in cardiovascular regulatory regions of the forebrain as an important molecular mediator of TNF-α-driven sympatho-excitatory responses and suggest that EGFR activation of the ERK1/2 signaling pathway plays an essential role. These mechanisms likely contribute to sympathetic excitation in pathophysiological states like heart failure and hypertension, in which circulating and brain TNF-α levels are increased.

中文翻译：

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TNF-α 诱导的交感神经兴奋需要前脑心血管调节区的 EGFR 和 ERK1/2 信号传导

外周或中枢给药的 TNF-α 引起延长的交感神经介导的升压反应，但潜在的分子机制尚不清楚。大脑心血管区域细胞外信号调节激酶 1 和 2 (ERK1/2) 的激活最近被认为是交感神经兴奋的关键介质，而 ERK1/2 信号传导是由表皮生长因子受体 (EGFR) 的激活诱导的酪氨酸激酶活性。本研究检查了 EGFR 和 ERK1/2 信号在对 TNF-α 的交感神经反应中的作用。在聚氨酯麻醉的大鼠中，颈动脉内注射 TNF-α 增加了穹窿下器官 (SFO) 和下丘脑室旁核 (PVN) 中 EGFR 和 ERK1/2 的磷酸化，上调了 SFO 和 PVN 中兴奋性介质的基因表达，并增加血压（BP）、心率（HR）和肾交感神经活动（RSNA）。选择性 EGFR 酪氨酸激酶抑制剂 AG1478 或 ERK1/2 抑制剂 PD98059 的连续脑室内输注显着减弱了这些反应。双侧 PVN 显微注射 TNF-α 也增加了 PVN 中磷酸化 ERK1/2 和兴奋性介质的基因表达，同时增加了 BP、HR 和 RSNA，并且这些反应因先前双侧 PVN 显微注射 AG1478 而显着降低。这些结果确定前脑心血管调节区域中 EGFR 的激活是 TNF-α 驱动的交感神经兴奋反应的重要分子介质，并表明 ERK1/2 信号通路的 EGFR 激活起着重要作用。