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Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus.
Circ Heart Fail. 2016 Jan; 9(1):e002261.CH

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.

Authors+Show Affiliations

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.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.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.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.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.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.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.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.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.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.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.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.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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26699387

Citation

Wang, Renjun, et al. "Sympathoexcitation in Rats With Chronic Heart Failure Depends On Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus." Circulation. Heart Failure, vol. 9, no. 1, 2016, pp. e002261.
Wang R, Huang Q, Zhou R, et al. Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus. Circ Heart Fail. 2016;9(1):e002261.
Wang, R., Huang, Q., Zhou, R., Dong, Z., Qi, Y., Li, H., Wei, X., Wu, H., Wang, H., Wilcox, C. S., Hultström, M., Zhou, X., & Lai, E. Y. (2016). Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus. Circulation. Heart Failure, 9(1), e002261. https://doi.org/10.1161/CIRCHEARTFAILURE.115.002261
Wang R, et al. Sympathoexcitation in Rats With Chronic Heart Failure Depends On Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus. Circ Heart Fail. 2016;9(1):e002261. PubMed PMID: 26699387.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus. AU - Wang,Renjun, AU - Huang,Qian, AU - Zhou,Rui, AU - Dong,Zengxiang, AU - Qi,Yunfeng, AU - Li,Hua, AU - Wei,Xiaowei, AU - Wu,Hui, AU - Wang,Huiping, AU - Wilcox,Christopher S, AU - Hultström,Michael, AU - Zhou,Xiaofu, AU - Lai,En Yin, Y1 - 2015/12/23/ PY - 2015/02/24/received PY - 2015/10/28/accepted PY - 2015/12/25/entrez PY - 2015/12/25/pubmed PY - 2016/4/28/medline KW - homeobox D10 KW - microRNA-7b KW - paraventricular nucleus KW - γ-aminobutyric acid SP - e002261 EP - e002261 JF - Circulation. Heart failure JO - Circ Heart Fail VL - 9 IS - 1 N2 - 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. SN - 1941-3297 UR - https://www.unboundmedicine.com/medline/citation/26699387/Sympathoexcitation_in_Rats_With_Chronic_Heart_Failure_Depends_on_Homeobox_D10_and_MicroRNA_7b_Inhibiting_GABBR1_Translation_in_Paraventricular_Nucleus_ L2 - https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.115.002261?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -