Tbx5-dependent Pathway Regulating Diastolic Function in Congenital Heart Disease

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2008 Apr 2

PMID 18378906

Citations 39

Authors

Yonghong Zhu

Anthony O Gramolini

Mark A Walsh

Yu-Qing Zhou

Cameron Slorach

Mark K Friedberg

Jun K Takeuchi

Hui Sun

R Mark Henkelman

Peter H Backx

Andrew N Redington

David H MacLennan

Benoit G Bruneau

Affiliations

Soon will be listed here.

Abstract

At the end of every heartbeat, cardiac myocytes must relax to allow filling of the heart. Impaired relaxation is a significant factor in heart failure, but all pathways regulating the cardiac relaxation apparatus are not known. Haploinsufficiency of the T-box transcription factor Tbx5 in mouse and man causes congenital heart defects (CHDs) as part of Holt-Oram syndrome (HOS). Here, we show that haploinsufficiency of Tbx5 in mouse results in cell-autonomous defects in ventricular relaxation. Tbx5 dosage modulates expression of the sarco(endo)plasmic reticulum Ca(2+)-ATPase isoform 2a encoded by Atp2a2 and Tbx5 haploinsufficiency in ventricular myocytes results in impaired Ca(2+) uptake dynamics and Ca(2+) transient prolongation. We also demonstrate that Tbx5 can activate the Atp2a2 promoter. Furthermore, we find that patients with HOS have significant diastolic filling abnormalities. These results reveal a direct genetic pathway that regulates cardiac diastolic function, implying that patients with structural CHDs may have clinically important underlying anomalies in heart function that merit treatment.

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