Endoplasmic reticulum stress increases brain MAPK signaling, inflammation and renin-angiotensin system activity and sympathetic nerve activity in heart failure
Endoplasmic reticulum stress increases brain MAPK signaling, inflammation and renin-angiotensin system activity and sympathetic nerve activity in heart failure
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DOI：
10.1152/ajpheart.00362.2016
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发表时间：
2016-10-01
影响因子：
4.8
通讯作者：
Felder, Robert B.
中科院分区：
文献类型：
--
作者：
Wei, Shun-Guang;Yu, Yang;Felder, Robert B.
我们先前报道，内质网应激在心力衰竭(HF)大鼠的穹隆下器(SFO)和下丘脑室旁核(PVN)诱导，并通过抑制丝裂原活化蛋白激酶(MAPK)信号转导而减轻。本研究进一步探讨了心衰时脑MAPK信号、内质网应激和交感神经兴奋之间的关系。假手术组(Sham)和心力衰竭大鼠(HF)侧脑室(Icv)注射Veh或内质网应激抑制剂牛磺酸脱氧胆酸(TUDCA，10mg.d)。TUDCA治疗的HF大鼠SFO和PVN中ER应激生物标志物GRP78、ATF6、ATF4和XBP-1s的mRNA水平降低，证实了TUDCA剂量的有效性。免疫印迹和免疫荧光染色显示，Veh处理的HF大鼠SFO和PVN中p44/42和p38MAPK的磷酸化水平明显低于Sham大鼠。与假手术组大鼠相比，Veh治疗的HF大鼠血浆去甲肾上腺素水平升高，而TUDCA治疗的HF大鼠血浆去甲肾上腺素水平显著降低。TUDCA治疗的心力衰竭大鼠在SFO和PVN中血管紧张素转换酶、血管紧张素II 1型受体、肿瘤坏死因子-α、白介素1β、环氧合酶-2和核因子-kappa B p65的mRNA水平也低于Veh治疗的心力衰竭大鼠，而I-kappa B-α的mRNA水平高于Veh治疗的心力衰竭大鼠。这些数据表明，内质网应激通过诱导MAPK信号，从而促进炎症和大脑关键心血管调节区的肾素-血管紧张素系统活动，从而促进心力衰竭交感神经活性的增强。
We previously reported that endoplasmic reticulum (ER) stress is induced in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN) of heart failure (HF) rats and is reduced by inhibition of mitogen-activated protein kinase (MAPK) signaling. The present study further examined the relationship between brain MAPK signaling, ER stress, and sympathetic excitation in HF. Sham-operated (Sham) and HF rats received a 4-wk intracerebroventricular (ICV) infusion of vehicle (Veh) or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 10 mu g/day). Lower mRNA levels of the ER stress biomarkers GRP78, ATF6, ATF4, and XBP-1s in the SFO and PVN of TUDCA-treated HF rats validated the efficacy of the TUDCA dose. The elevated levels of phosphorylated p44/42 and p38 MAPK in SFO and PVN of Veh-treated HF rats, compared with Sham rats, were significantly reduced in TUDCA-treated HF rats as shown by Western blot and immunofluorescent staining. Plasma norepinephrine levels were higher in Veh-treated HF rats, compared with Veh-treated Sham rats, and were significantly lower in the TUDCA-treated HF rats. TUDCA-treated HF rats also had lower mRNA levels for angiotensin converting enzyme, angiotensin II type 1 receptor, tumor necrosis factor-alpha, interleukin-1 beta, cyclooxygenase-2, and NF-kappa B p65, and a higher mRNA level of I kappa B-alpha, in the SFO and PVN than Veh-treated HF rats. These data suggest that ER stress contributes to the augmented sympathetic activity in HF by inducing MAPK signaling, thereby promoting inflammation and renin-angiotensin system activity in key cardiovascular regulatory regions of the brain.