title: Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus.
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.
  
  
  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.affiliation: 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.
authors.forename: Renjun
authors.initials: R
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Zengxiang
authors.initials: Z
authors.lastname: Dong
authors.affiliation: 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.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Qi
authors.affiliation: 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.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wei
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Huiping
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilcox
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Hultström
authors.affiliation: 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.
authors.forename: Xiaofu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: En Yin
authors.initials: EY
authors.lastname: Lai
mesh_terms: D020413:3' Untranslated Regions; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002908:Chronic Disease; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D034622:RNA Interference; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D047228:Angiotensin II Type 1 Receptor Blockers; C000607057:HOXD10 protein, rat; D018398:Homeodomain Proteins; C490944:Hoxd10 protein, mouse; C548145:MIRNLET7 microRNA, rat; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D044140:Receptor, Angiotensin, Type 1; D018080:Receptors, GABA-B; D014157:Transcription Factors; C542687:mirnlet7 microRNA, mouse; D000804:Angiotensin II; D019808:Losartan
keywords: homeobox D10; microRNA-7b; paraventricular nucleus; γ-aminobutyric acid