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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  ;  Hui-Nam Pak  ;  Moon-Hyoung Lee  ;  Hail Kim  ;  Boyoung Joung 
 CIRCULATION JOURNAL, Vol.79(8) : 1807-1815, 2015 
Journal Title
Issue Date
Animals ; Arrhythmias, Cardiac/genetics ; Arrhythmias, Cardiac/metabolism ; Death, Sudden, Cardiac* ; Female ; Mice ; Mice, Knockout ; Myocardium/metabolism* ; Myocardium/pathology ; Pregnancy ; Pregnancy Complications, Cardiovascular/genetics ; Pregnancy Complications, Cardiovascular/metabolism* ; Receptors, Serotonin, 5-HT3/deficiency* ; Serotonin/biosynthesis* ; Serotonin/genetics ; Tryptophan Hydroxylase/genetics ; Tryptophan Hydroxylase/metabolism*
Fatal arrhythmia ; Pregnancy ; QT prolongation ; Serotonin receptor type 3
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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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
Yonsei Authors
Park, Jun Beom(박준범)
Park, Hye Lim(박혜림)
Park, Hye Won(박혜원)
Pak, Hui Nam(박희남) ORCID logo https://orcid.org/0000-0002-3256-3620
Lee, Moon-Hyoung(이문형) ORCID logo https://orcid.org/0000-0002-7268-0741
Joung, Bo Young(정보영) ORCID logo https://orcid.org/0000-0001-9036-7225
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