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Tbx5-dependent pathway regulating diastolic function in congenital heart disease

Yonghong Zhu1, Anthony O Gramolini, Mark A Walsh

  • 1Programme in Developmental and Stem Cell Biology, Division of Cardiology and Labatt Family Heart Centre, Programme in Physiology and Experimental Medicine, and Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada.

Proceedings of the National Academy of Sciences of the United States of America
|April 2, 2008
PubMed

Insights

T-box transcription factor Tbx5 deficiency impairs cardiac myocyte relaxation. Tbx5 dosage regulates the sarco(endo)plasmic reticulum Ca2+-ATPase, impacting heart failure and congenital heart defects.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Developmental Biology

Background:

  • Cardiac myocyte relaxation is crucial for heart function.
  • Impaired relaxation contributes significantly to heart failure.
  • The complete regulatory pathways for cardiac relaxation are not fully understood.

Purpose of the Study:

  • To investigate the role of T-box transcription factor 5 (Tbx5) in cardiac myocyte relaxation.
  • To determine if Tbx5 haploinsufficiency causes cell-autonomous defects in ventricular relaxation.
  • To elucidate the molecular mechanisms by which Tbx5 regulates cardiac diastolic function.

Main Methods:

  • Utilized a mouse model of Tbx5 haploinsufficiency.
  • Assessed cell-autonomous ventricular relaxation.
  • Quantified sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2a (Atp2a2) expression and activity.
  • Performed promoter activity assays for Atp2a2.
  • Evaluated diastolic filling in Holt-Oram syndrome patients.

Main Results:

  • Tbx5 haploinsufficiency in mice leads to cell-autonomous defects in ventricular relaxation.
  • Tbx5 dosage modulates the expression of Atp2a2.
  • Tbx5 directly activates the Atp2a2 promoter.
  • Tbx5 haploinsufficiency results in impaired Ca2+ uptake dynamics and prolonged Ca2+ transients in ventricular myocytes.
  • Holt-Oram syndrome patients exhibit significant diastolic filling abnormalities.

Conclusions:

  • Tbx5 plays a direct role in regulating cardiac diastolic function.
  • A genetic pathway involving Tbx5 and Atp2a2 is critical for cardiac relaxation.
  • Patients with congenital heart defects associated with Tbx5 mutations may have underlying diastolic dysfunction that requires clinical attention.

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