Deletion of the serotonin receptor type 3A in mice leads to sudden cardiac death during pregnancy

Hyewon Park, Chang Myung Oh, Junbeom Park, Hyelim Park, Shanyu Cui, Hyung Suk Kim, Jun Namkung, Sang Kyu Park, huinam pak, Moon Hyoung Lee, Hail Kim, Boyoung Joung

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Abstract

Background: The serotonin receptor type 3 (Htr3) blocker is associated with QT prolongation and torsades de pointes. However, little is known about effects of Htr3 on the heart arrhythmia. Methods and Results: An electrophysiological study Involving knock-out (KO) female mice lacking functional Htr3a (Htr3a–/–) and their wild-type littermates during non-pregancy (NP) and late pregnancy (LP) was performed. Htr3a mRNA was present in the wild-type, but not in the Htr3a–/– mouse hearts. Serotonin and tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme of serotonin synthesis in hearts, is increased during pregnancy. The heart weight and size were increased in the pregnant mice regardless of a mutation. The QTc intervals were prolonged after pregnancy in both the wild (NP: 171.2 ±16.8 vs. LP: 247.7±14.3 ms; P<0.001) and Htr3a–/– mice (NP: 187.9±18.7 vs. LP: 275.6±11.0 ms, P<0.001). Compared with wild-type LP mice, Htr3a–/– LP mice had increased spontaneous ventricle tarchycardia (VT; 56% vs. 0%, P=0.002), VT inducibility (66% vs. 25%, P=0.002) and mortality (56% vs. 0%, P=0.002). Pharmacologic administration of serotonin and Htr3 agonists (m-CPBG) decreased the QT interval in wild mice, but not in Htr3a–/– mice. Conclusions: Htr3a is present in mouse hearts. Serotonin and Tph1 were increased during pregnancy. The deletion of Htr3a was related to fatal arrhythmias and sudden cardiac death during pregnancy, and its activation reversed the QT prolongation.

Original languageEnglish
Pages (from-to)1807-1815
Number of pages9
JournalCirculation Journal
Volume79
Issue number8
DOIs
Publication statusPublished - 2015 Jul 24

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Serotonin Receptors
Sudden Cardiac Death
Pregnancy
Tryptophan Hydroxylase
Serotonin
Cardiac Arrhythmias
Prolonged Pregnancy
Torsades de Pointes
Receptors, Serotonin, 5-HT3
Serotonin Receptor Agonists
Knockout Mice
Weights and Measures
Messenger RNA
Mutation
Mortality
Enzymes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Park, Hyewon ; Oh, Chang Myung ; Park, Junbeom ; Park, Hyelim ; Cui, Shanyu ; Kim, Hyung Suk ; Namkung, Jun ; Park, Sang Kyu ; pak, huinam ; Lee, Moon Hyoung ; Kim, Hail ; Joung, Boyoung. / Deletion of the serotonin receptor type 3A in mice leads to sudden cardiac death during pregnancy. In: Circulation Journal. 2015 ; Vol. 79, No. 8. pp. 1807-1815.
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title = "Deletion of the serotonin receptor type 3A in mice leads to sudden cardiac death during pregnancy",
abstract = "Background: The serotonin receptor type 3 (Htr3) blocker is associated with QT prolongation and torsades de pointes. However, little is known about effects of Htr3 on the heart arrhythmia. Methods and Results: An electrophysiological study Involving knock-out (KO) female mice lacking functional Htr3a (Htr3a–/–) and their wild-type littermates during non-pregancy (NP) and late pregnancy (LP) was performed. Htr3a mRNA was present in the wild-type, but not in the Htr3a–/– mouse hearts. Serotonin and tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme of serotonin synthesis in hearts, is increased during pregnancy. The heart weight and size were increased in the pregnant mice regardless of a mutation. The QTc intervals were prolonged after pregnancy in both the wild (NP: 171.2 ±16.8 vs. LP: 247.7±14.3 ms; P<0.001) and Htr3a–/– mice (NP: 187.9±18.7 vs. LP: 275.6±11.0 ms, P<0.001). Compared with wild-type LP mice, Htr3a–/– LP mice had increased spontaneous ventricle tarchycardia (VT; 56{\%} vs. 0{\%}, P=0.002), VT inducibility (66{\%} vs. 25{\%}, P=0.002) and mortality (56{\%} vs. 0{\%}, P=0.002). Pharmacologic administration of serotonin and Htr3 agonists (m-CPBG) decreased the QT interval in wild mice, but not in Htr3a–/– mice. Conclusions: Htr3a is present in mouse hearts. Serotonin and Tph1 were increased during pregnancy. The deletion of Htr3a was related to fatal arrhythmias and sudden cardiac death during pregnancy, and its activation reversed the QT prolongation.",
author = "Hyewon Park and Oh, {Chang Myung} and Junbeom Park and Hyelim Park and Shanyu Cui and Kim, {Hyung Suk} and Jun Namkung and Park, {Sang Kyu} and huinam pak and Lee, {Moon Hyoung} and Hail Kim and Boyoung Joung",
year = "2015",
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Park, H, Oh, CM, Park, J, Park, H, Cui, S, Kim, HS, Namkung, J, Park, SK, pak, H, Lee, MH, Kim, H & Joung, B 2015, 'Deletion of the serotonin receptor type 3A in mice leads to sudden cardiac death during pregnancy', Circulation Journal, vol. 79, no. 8, pp. 1807-1815. https://doi.org/10.1253/circj.CJ-14-1074

Deletion of the serotonin receptor type 3A in mice leads to sudden cardiac death during pregnancy. / Park, Hyewon; Oh, Chang Myung; Park, Junbeom; Park, Hyelim; Cui, Shanyu; Kim, Hyung Suk; Namkung, Jun; Park, Sang Kyu; pak, huinam; Lee, Moon Hyoung; Kim, Hail; Joung, Boyoung.

In: Circulation Journal, Vol. 79, No. 8, 24.07.2015, p. 1807-1815.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Deletion of the serotonin receptor type 3A in mice leads to sudden cardiac death during pregnancy

AU - Park, Hyewon

AU - Oh, Chang Myung

AU - Park, Junbeom

AU - Park, Hyelim

AU - Cui, Shanyu

AU - Kim, Hyung Suk

AU - Namkung, Jun

AU - Park, Sang Kyu

AU - pak, huinam

AU - Lee, Moon Hyoung

AU - Kim, Hail

AU - Joung, Boyoung

PY - 2015/7/24

Y1 - 2015/7/24

N2 - Background: The serotonin receptor type 3 (Htr3) blocker is associated with QT prolongation and torsades de pointes. However, little is known about effects of Htr3 on the heart arrhythmia. Methods and Results: An electrophysiological study Involving knock-out (KO) female mice lacking functional Htr3a (Htr3a–/–) and their wild-type littermates during non-pregancy (NP) and late pregnancy (LP) was performed. Htr3a mRNA was present in the wild-type, but not in the Htr3a–/– mouse hearts. Serotonin and tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme of serotonin synthesis in hearts, is increased during pregnancy. The heart weight and size were increased in the pregnant mice regardless of a mutation. The QTc intervals were prolonged after pregnancy in both the wild (NP: 171.2 ±16.8 vs. LP: 247.7±14.3 ms; P<0.001) and Htr3a–/– mice (NP: 187.9±18.7 vs. LP: 275.6±11.0 ms, P<0.001). Compared with wild-type LP mice, Htr3a–/– LP mice had increased spontaneous ventricle tarchycardia (VT; 56% vs. 0%, P=0.002), VT inducibility (66% vs. 25%, P=0.002) and mortality (56% vs. 0%, P=0.002). Pharmacologic administration of serotonin and Htr3 agonists (m-CPBG) decreased the QT interval in wild mice, but not in Htr3a–/– mice. Conclusions: Htr3a is present in mouse hearts. Serotonin and Tph1 were increased during pregnancy. The deletion of Htr3a was related to fatal arrhythmias and sudden cardiac death during pregnancy, and its activation reversed the QT prolongation.

AB - Background: The serotonin receptor type 3 (Htr3) blocker is associated with QT prolongation and torsades de pointes. However, little is known about effects of Htr3 on the heart arrhythmia. Methods and Results: An electrophysiological study Involving knock-out (KO) female mice lacking functional Htr3a (Htr3a–/–) and their wild-type littermates during non-pregancy (NP) and late pregnancy (LP) was performed. Htr3a mRNA was present in the wild-type, but not in the Htr3a–/– mouse hearts. Serotonin and tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme of serotonin synthesis in hearts, is increased during pregnancy. The heart weight and size were increased in the pregnant mice regardless of a mutation. The QTc intervals were prolonged after pregnancy in both the wild (NP: 171.2 ±16.8 vs. LP: 247.7±14.3 ms; P<0.001) and Htr3a–/– mice (NP: 187.9±18.7 vs. LP: 275.6±11.0 ms, P<0.001). Compared with wild-type LP mice, Htr3a–/– LP mice had increased spontaneous ventricle tarchycardia (VT; 56% vs. 0%, P=0.002), VT inducibility (66% vs. 25%, P=0.002) and mortality (56% vs. 0%, P=0.002). Pharmacologic administration of serotonin and Htr3 agonists (m-CPBG) decreased the QT interval in wild mice, but not in Htr3a–/– mice. Conclusions: Htr3a is present in mouse hearts. Serotonin and Tph1 were increased during pregnancy. The deletion of Htr3a was related to fatal arrhythmias and sudden cardiac death during pregnancy, and its activation reversed the QT prolongation.

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