Cyclin D2 rescues size and function of GATA4 haplo-insufficient hearts

Am J Physiol Heart Circ Physiol. 2012 Oct 15;303(8):H1057-66. doi: 10.1152/ajpheart.00250.2012. Epub 2012 Aug 24.


Transcription factor GATA4 is a key regulator of cardiomyocyte growth, and differentiation and 50% reduction in GATA4 levels results in hypoplastic hearts. Search for GATA4 targets/effectors revealed cyclin D(2) (CD2), a member of the D-type cyclins (D(1), D(2), and D(3)) that play a vital role in cell growth and differentiation as a direct transcriptional target and a mediator of GATA4 growth in postnatal cardiomyocytes. GATA4 associates with the CD2 promoter in cardiomyocytes and is sufficient to induce endogenous CD2 transcription and to dose-dependently activate the CD2 promoter in heterologous cells. Cardiomyocyte-specific overexpression of CD2 results in enhanced postnatal cardiac growth because of increased cardiomyocyte proliferation. When these transgenic mice are crossed with Gata4 heterozygote mice, they rescue the hypoplastic cardiac phenotype of Gata4(+/-) mice and enhance cardiomyocyte survival and heart function. The data uncover a role for CD2 in the postnatal heart as an effector of GATA4 in myocyte growth and survival. The finding that postnatal upregulation of a cell-cycle gene in GATA4 haplo-insufficient hearts may be protective opens new avenues for maintaining or restoring cardiac function in GATA4-dependent cardiac disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • CD2 Antigens / genetics
  • CD2 Antigens / metabolism
  • Cardiomegaly / metabolism
  • Cardiomegaly / physiopathology*
  • Cell Proliferation
  • Cyclin D2 / genetics
  • Cyclin D2 / metabolism*
  • GATA4 Transcription Factor / genetics*
  • GATA4 Transcription Factor / metabolism*
  • Gene Expression Regulation, Developmental / physiology
  • HEK293 Cells
  • Haplotypes
  • Heart / embryology
  • Heart / physiology
  • Humans
  • Mice
  • Mice, Transgenic
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / physiology*
  • NIH 3T3 Cells
  • Phenotype
  • Rats
  • Rats, Sprague-Dawley
  • Transcription, Genetic / physiology


  • CD2 Antigens
  • Ccnd2 protein, mouse
  • Cyclin D2
  • GATA4 Transcription Factor
  • Gata4 protein, mouse
  • Gata4 protein, rat