This allele contains a deletion of the second coding exon of Gata4, including the start codon and the Nterminal 46% of the coding region. The mice used in this study were all male and on a uniform F1 genetic background resulting from the cross of Gata4WT/Δex2 (abbreviated G4D) mice, backcrossed for greater than 8 generations into C57BL6/J, to wild-type FVB/N mice. G4D progeny from this cross were present at weaning at the expected Mendelian ratio (104/218, 48%), survived normally to 18 months of age, and had no evidence of structural heart disease (0 out of 15 embryos examined histologically at E15.5-E18.5). Gata4WT/WT littermates (WT) from these crosses were used as controls.
Treatment protocol
The ligature for aortic banding was sized by tying around a 27 gauge needle. The ligature was placed on the transverse aorta between the brachiocephalic trunk and the left common carotid artery. The identical procedure was used for sham operation, except that the aorta was not manipulated.
Extracted molecule
total RNA
Label
Biotin
Description
An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiac cardiomyocytes, the transcription factor Gata4 is required for agonist-induced cardiomyocyte hypertrophy. We hypothesized that in the intact organism Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed upregulation of genes associated with apoptosis and fibrosis, including members of the TGFβ pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from loadinduced failure.
