Transforming Growth Factor-α Acts in Hypothalamic Paraventricular Nucleus to Upregulate ERK1/2 Signaling and Expression of Sympathoexcitatory Mediators in Heart Failure Rats.
Transforming Growth Factor-α Acts in Hypothalamic Paraventricular Nucleus to Upregulate ERK1/2 Signaling and Expression of Sympathoexcitatory Mediators in Heart Failure Rats.
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DOI：
10.1016/j.neuroscience.2021.12.030
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发表时间：
2022-02-10
期刊：
影响因子：
3.3
通讯作者：
Wei SG
中科院分区：
文献类型：
--
作者：
Yu Y;Chen E;Weiss RM;Felder RB;Wei SG
表皮生长因子受体（EGFR）酪氨酸激酶的激活与下丘脑室旁核（PVN）细胞外信号调节激酶（ERK） 1/2信号的增加有关，这有助于心力衰竭（HF）的交感兴奋。转化生长因子(TGF)-α是EGFR的主要内源性配体。本研究旨在确定TGF-α是否增加HF的PVN，并促进EGFR的激活以增加ERK1/2活性。雄性大鼠双侧PVN显微注射EGFR siRNA或重组siRNA，一周后脑室内（ICV）注射TGF-α或载体。与未处理的年龄相匹配的对照大鼠相比，ICV TGF-α增加了磷酸化的（p-） EGFR，上调了PVN中p- erk1 /2的表达和促炎细胞因子（PICs）和肾素血管紧张素系统（RAS）成分的mRNA水平。经EGFR siRNA预处理的大鼠对ICV TGF-α的反应明显减弱。此外，与搅合siRNA处理的HF大鼠相比，双侧PVN显微注射TGF-α siRNA显著降低了PVN中TGF-α、p-EGFR、p-ERK1/2的升高水平以及PICs和RAS成分的mRNA表达。TGF-α sirna处理的HF大鼠也表现出较低的血浆去甲肾上腺素水平和改善的HF外周表现。这些数据表明，TGF-α在HF的PVN中表达上调，并诱导egfr介导的ERK1/2信号的激活，从而增强HF的炎症和RAS活性，从而驱动交感神经兴奋。
Activation of epidermal growth factor receptor (EGFR) tyrosine kinase is associated with increased extracellular signal-regulated kinase (ERK) 1/2 signaling in the hypothalamic paraventricular nucleus (PVN), which contributes to the sympathetic excitation in heart failure (HF). Transforming growth factor (TGF)-α is a major endogenous ligand for EGFR. The present study sought to determine whether TGF-α increases in the PVN in HF and promotes the activation of EGFR to increase ERK1/2 activity. Male rats received bilateral PVN microinjections of an EGFR siRNA or a scrambled siRNA followed by an intracerebroventricular (ICV) injection of TGF-α or vehicle one week later. In rats pretreated with the scrambled siRNA, ICV TGF-α increased phosphorylated (p-) EGFR and upregulated the expression of p-ERK1/2 and mRNA levels of proinflammatory cytokines (PICs) and renin-angiotensin system (RAS) components in the PVN, when compared with the untreated age-matched control rats. These responses to ICV TGF-α were significantly attenuated in rats pretreated with the EGFR siRNA. Furthermore, bilateral PVN microinjections of a TGF-α siRNA in HF rats significant decreased the elevated levels of TGF-α, p-EGFR, p-ERK1/2 and the mRNA expression of PICs and RAS components in the PVN, compared with the HF rats treated with a scrambled siRNA. The TGF-α siRNA-treated HF rats also exhibited lower plasma norepinephrine levels and improved peripheral manifestations of HF. These data suggest that TGF-α expression is upregulated in the PVN in HF and induces the activation of EGFR-mediated ERK1/2 signaling to augment the inflammation and RAS activity that drives sympathetic excitation in HF.
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影响因子：
5.5
作者：
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通讯作者：
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影响因子：
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