Wang Renjun, Huang Qian, Zhou Rui, Dong Zengxiang, Qi Yunfeng, Li Hua, Wei Xiaowei, Wu Hui, Wang Huiping, Wilcox Christopher S, Hultström Michael, Zhou Xiaofu, Lai En Yin
From the Departments of Biotechnology (R.W., H.L, H. Wu) and Bioscience (Y.Q., X.W., X.Z.), School of Life Science, Jilin Normal University, Siping, China; Key Laboratory of Cardiovascular Medicine Research of Ministry of Education, Harbin Medical University, Harbin, China (R.W.); Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (Q.H., R.Z., H. Wang, E.Y.L.); Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, China (Z.D.); Department of Medicine, Division of Nephrology and Hypertension, and Hypertension, Kidney and Vascular Health Center, Georgetown University, Washington, DC (C.S.W.); and Integrative Physiology, Department of Medical Cell Biology (M.H.) and Anaesthesia and Intensive Care Medicine, Department of Surgical Sciences (M.H.), Uppsala University, Uppsala, Sweden.
Circ Heart Fail. 2016 Jan;9(1):e002261. doi: 10.1161/CIRCHEARTFAILURE.115.002261. Epub 2015 Dec 23.
Chronic heart failure (CHF) increases sympathoexcitation through angiotensin II (ANG II) receptors (AT1R) in the paraventricular nucleus (PVN). Recent publications indicate both γ-aminobutyric acid B-type receptor 1 (GABBR1) and microRNA-7b (miR-7b) are expressed in the PVN. We hypothesized that ANG II regulates sympathoexcitation through homeobox D10 (HoxD10), which regulates miR-7b in other tissues.
Ligation of the left anterior descendent coronary artery in rats caused CHF and sympathoexcitation. PVN expression of AT1R, HoxD10, and miR-7b was increased, whereas GABBR1 was lower in CHF. Infusion of miR-7b in the PVN caused sympathoexcitation in control animals and enhanced the changes in CHF. Antisense miR-7b infused in PVN normalized GABBR1 expression while attenuating CHF symptoms, including sympathoexcitation. A luciferase reporter assay detected miR-7b binding to the 3' untranslated region of GABBR1 that was absent after targeted mutagenesis. ANG II induced HoxD10 and miR-7b in NG108 cells, effects blocked by AT1R blocker losartan and by HoxD10 silencing. miR-7b transfection into NG108 cells decreased GABBR1 expression, which was inhibited by miR-7b antisense. In vivo PVN knockdown of AT1R attenuated the symptoms of CHF, whereas HoxD10 overexpression exaggerated them. Finally, in vivo PVN ANG II infusion caused dose-dependent sympathoexcitation that was abrogated by miR-7b antisense and exaggerated by GABBR1 silencing.
There is an ANG II/AT1R/HoxD10/miR-7b/GABBR1 pathway in the PVN that contributes to sympathoexcitation and deterioration of cardiac function in CHF.
慢性心力衰竭（CHF）通过室旁核（PVN）中的血管紧张素II（ANG II）受体（AT1R）增加交感神经兴奋。最近的出版物表明γ-氨基丁酸B型受体1（GABBR1）和微小RNA-7b（miR-7b）均在PVN中表达。我们假设ANG II通过同源盒D10（HoxD10）调节交感神经兴奋，而HoxD10在其他组织中调节miR-7b。
大鼠左前降支冠状动脉结扎导致CHF和交感神经兴奋。CHF时PVN中AT1R、HoxD10和miR-7b的表达增加，而GABBR1的表达降低。向PVN中注入miR-7b在对照动物中引起交感神经兴奋，并增强CHF中的变化。向PVN中注入反义miR-7b可使GABBR1表达正常化，同时减轻CHF症状，包括交感神经兴奋。荧光素酶报告基因检测发现miR-7b与GABBR1的3'非翻译区结合，靶向诱变后该结合消失。ANG II在NG108细胞中诱导HoxD10和miR-7b，血管紧张素II受体阻滞剂氯沙坦和HoxD10沉默可阻断这些作用。将miR-7b转染到NG108细胞中可降低GABBR1表达，而miR-7b反义寡核苷酸可抑制该作用。体内PVN中AT1R的敲低减轻了CHF症状，而HoxD10的过表达则使其加重。最后，体内PVN中注入ANG II引起剂量依赖性交感神经兴奋，miR-7b反义寡核苷酸可消除该兴奋，而GABBR1沉默则使其增强。
PVN中存在ANG II/AT1R/HoxD10/miR-7b/GABBR1途径，该途径导致CHF中的交感神经兴奋和心功能恶化。
