Renjun Wang1, Qian Huang1, Rui Zhou1, Zengxiang Dong1, Yunfeng Qi1, Hua Li1, Xiaowei Wei1, Hui Wu1, Huiping Wang1, Christopher S Wilcox1, Michael Hultström1, Xiaofu Zhou1, En Yin Lai2. 1. 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. 2. 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. laienyin@zju.edu.cn.
Abstract
BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
Authors: J N Cohn; T B Levine; M T Olivari; V Garberg; D Lura; G S Francis; A B Simon; T Rector Journal: N Engl J Med Date: 1984-09-27 Impact factor: 91.245