Silencing Epidermal Growth Factor Receptor in Hypothalamic Paraventricular Nucleus Reduces Extracellular Signal-regulated Kinase 1 and 2 Signaling and Sympathetic Excitation in Heart Failure Rats.
Silencing Epidermal Growth Factor Receptor in Hypothalamic Paraventricular Nucleus Reduces Extracellular Signal-regulated Kinase 1 and 2 Signaling and Sympathetic Excitation in Heart Failure Rats.
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沉默下丘脑室旁核表皮生长因子受体可降低心力衰竭大鼠细胞外信号调节激酶1和2的信号转导和交感神经兴奋。
DOI：
10.1016/j.neuroscience.2021.01.025
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发表时间：
2021-05-21
期刊：
影响因子：
3.3
通讯作者：
Felder RB
中科院分区：
文献类型：
--
作者：
Yu Y;Wei SG;Weiss RM;Felder RB
脑心血管调节区域ERK1/2信号的激活通过增加脑肾素-血管紧张素系统（RAS）活性、神经炎症和内质网（ER）应激，有助于心肌梗死（MI）诱导心力衰竭（HF）的交感兴奋。在HF中引发脑ERK1/2信号的机制仍然知之甚少。我们测试了表皮生长因子受体（EGFR）的参与，EGFR在激活后会刺激ERK1/2的活性。成年雄性Sprague-Dawley大鼠接受双侧微注射，将编码EGFR小干扰RNA （siRNA）的慢病毒载体或混乱的siRNA注入下丘脑室旁核（PVN）， PVN是心衰交感过度活动的公认来源。1周后行冠状动脉结扎术诱导心衰。4周后，与干扰sirna处理的HF大鼠相比，EGFR - sirna处理的HF大鼠EGFR mRNA和蛋白水平较低，磷酸化（p-） EGFR和p- erk1 /2水平较低，PVN中炎症介质TNF-α、IL-1β和环氧化酶-2、RAS成分血管紧张素转换酶和血管紧张素II型1a受体以及内质网应激标志物BIP和ATF4 mRNA水平较低。他们的血浆和尿去甲肾上腺素水平也较低，心衰的外周表现也有所改善。进一步的研究显示，与假手术对照大鼠相比，HF大鼠PVN中的p-EGFR升高。这些结果表明，在心肌梗死诱导的HF中，PVN中EGFR的激活会触发ERK1/2信号，以及内质网应激、神经炎症和RAS活性。脑EGFR可能是心肌梗死性心衰治疗干预的新靶点。
Activation of ERK1/2 signaling in cardiovascular regulatory regions of the brain contributes to sympathetic excitation in myocardial infarction (MI)-induced heart failure (HF) by increasing brain renin-angiotensin system (RAS) activity, neuroinflammation, and endoplasmic reticulum (ER) stress. The mechanisms eliciting brain ERK1/2 signaling in HF are still poorly understood. We tested the involvement of the epidermal growth factor receptor (EGFR) which, upon activation, stimulates ERK1/2 activity. Adult male Sprague-Dawley rats received bilateral microinjections of a lentiviral vector encoding a small interfering RNA (siRNA) for EGFR, or a scrambled siRNA, into the hypothalamic paraventricular nucleus (PVN), a recognized source of sympathetic overactivity in HF. One week later, coronary artery ligation was performed to induce HF. Four weeks later, the EGFR siRNA-treated HF rats, compared with the scrambled siRNA-treated HF rats, had lower mRNA and protein levels of EGFR, lower levels of phosphorylated (p-) EGFR and p-ERK1/2 and lower mRNA levels of the inflammatory mediators TNF-α, IL-1β and cyclooxygenase-2, the RAS components angiotensin-converting enzyme and angiotensin II type 1a receptor and the ER stress markers BIP and ATF4 in the PVN. They also had lower plasma and urinary norepinephrine levels and improved peripheral manifestations of HF. Additional studies revealed that p-EGFR was increased in the PVN of HF rats, compared with sham-operated control rats. These results suggest that activation of EGFR in the PVN triggers ERK1/2 signaling, along with ER stress, neuroinflammation and RAS activity, in MI-induced HF. Brain EGFR may be a novel target for therapeutic intervention in MI-induced HF.
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影响因子：
5.5
作者：
Sonner, Patrick A.;Stern, Javier E.
通讯作者：
Stern, Javier E.
DOI：
10.1161/hypertensionaha.115.05344
发表时间：
2015-06
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Takayanagi T;Kawai T;Forrester SJ;Obama T;Tsuji T;Fukuda Y;Elliott KJ;Tilley DG;Davisson RL;Park JY;Eguchi S
通讯作者：
Eguchi S
影响因子：
5.8
作者：
Jamroz-Wisniewska, Anna;Wojcicka, Grazyna;Beltowski, Jerzy
通讯作者：
Beltowski, Jerzy
DOI：
10.1152/ajpheart.00317.2009
发表时间：
2009-09-01
影响因子：
4.8
作者：
Huang, Bing S.;Ahmad, Monir;Leenen, Frans H. H.
通讯作者：
Leenen, Frans H. H.
影响因子：
10.8
作者：
Kang, Yu-Ming;Ma, Ying;Francis, Joseph
通讯作者：
Francis, Joseph