GATA-4 is an angiogenic survival factor of the infarcted heart.
BACKGROUND
Recent data suggest that GATA-4 is an antiapoptotic factor required for adaptive responses and a key regulator of hypertrophy and hypertrophy-associated genes in the heart. As a leading cause of chronic heart failure, reversal of postinfarction left ventricular remodeling represents an important target for therapeutic interventions. Here, we studied the role of GATA-4 as a mediator of postinfarction remodeling in rats.


RESULTS
Myocardial infarction, caused by ligating the left anterior descending coronary artery, significantly decreased the DNA binding activity of GATA-4 at day 1, whereas at 2 weeks the GATA-4 DNA binding was significantly upregulated. To determine the functional role of GATA-4, peri-infarct intramyocardial delivery of adenoviral vector expressing GATA-4 was done before left anterior descending coronary artery ligation. Hearts treated with GATA-4 gene transfer exhibited significantly increased ejection fraction and fractional shortening. Accordingly, infarct size was significantly reduced. To determine the cardioprotective mechanisms of GATA-4, myocardial angiogenesis, rate of apoptosis, c-kit+ cardiac stemlike cells, and genes regulated by GATA-4 were studied. The number of capillaries and stemlike cells was significantly increased, and decreased apoptosis was observed.


CONCLUSIONS
These results indicate that the reversal of reduced GATA-4 activity prevents adverse postinfarction remodeling through myocardial angiogenesis, antiapoptosis, and stem cell recruitment. GATA-4-based gene transfer may represent a novel, efficient therapeutic approach for heart failure.
Rysä
Jaana
J
Department of Pharmacology and Toxicology, Institute of Biomedicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
Tenhunen
Olli
O
Serpi
Raisa
R
Soini
Ylermi
Y
Nemer
Mona
M
Leskinen
Hanna
H
Ruskoaho
Heikki
H
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D050991:GATA4 Transcription Factor / Q000502:physiology*; D018014:Gene Transfer Techniques; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology* / Q000503:physiopathology* / Q000628:therapy; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000502:physiology*
D050991:GATA4 Transcription Factor