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Tbx5-dependent pathway regulating diastolic function in congenital heart disease.

Authors
  • 1
Type
Published Article
Journal
Proceedings of the National Academy of Sciences of the United States of America
1091-6490
Publication Date
Volume
105
Issue
14
Pages
5519–5524
Identifiers
DOI: 10.1073/pnas.0801779105
PMID: 18378906
Source
Medline

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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