Tbx5-dependent pathway regulating diastolic function in congenital heart disease

doi:10.1073/pnas.0801779105

Tbx5-dependent pathway regulating diastolic function in congenital heart disease

^aProgramme in Developmental and Stem Cell Biology,
^eDivision of Cardiology and Labatt Family Heart Centre,
^kProgramme in Physiology and Experimental Medicine, and
^fMouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8;
^cBanting and Best Department of Medical Research, Charles H. Best Institute, University of Toronto, 112 College Street, Toronto, ON, Canada M5G 1L6;
^bHeart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada, M5S 3E2;
Departments of ^dPhysiology,
^mMolecular and Medical Genetics,
^hMedical Biophysics, and
ⁱMedicine, University of Toronto, Toronto, ON, Canada M5S 1A8;
^jDivision of Cardiology, University Health Network, 190 Elizabeth Street, Toronto, ON, Canada M5G 2C4; and
^gGladstone Institute of Cardiovascular Disease, Department of Pediatrics, University of California, San Francisco, CA 94158

Contributed by David H. MacLennan, February 22, 2008 (received for review November 7, 2007)

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 Ca²⁺-ATPase isoform 2a encoded by Atp2a2 and Tbx5 haploinsufficiency in ventricular myocytes results in impaired Ca²⁺ uptake dynamics and Ca²⁺ 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.

Footnotes

^lTo whom correspondence may be addressed. E-mail: david.maclennan{at}utoronto.ca or bbruneau{at}gladstone.ucsf.edu
Author contributions: Y.Z. and A.O.G. contributed equally to this work; A.O.G., P.H.B., A.N.R., and B.G.B. designed research; Y.Z., A.O.G., M.A.W., Y.-Q.Z., C.S., M.K.F., J.K.T., and H.S. performed research; R.M.H. contributed new reagents/analytic tools; Y.Z., A.O.G., M.A.W., Y.-Q.Z., J.K.T., H.S., P.H.B., A.N.R., D.H.M., and B.G.B. analyzed data; and A.O.G., D.H.M., and B.G.B. wrote the paper;.
The authors declare no conflict of interest.