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Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus
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2016 (English)In: Circulation Heart Failure, ISSN 1941-3289, E-ISSN 1941-3297, Vol. 9, no 1, e002261Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 9, no 1, e002261
Keyword [en]
gamma-aminobutyric acid; homeobox D10; microRNA-7b; paraventricular nucleus
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URN: urn:nbn:se:uu:diva-272536DOI: 10.1161/CIRCHEARTFAILURE.115.002261ISI: 000368617200001PubMedID: 26699387OAI: oai:DiVA.org:uu-272536DiVA: diva2:894367
Available from: 2016-01-14 Created: 2016-01-14 Last updated: 2016-02-23Bibliographically approved

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Hultström, Michael
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