GATA-4 is an angiogenic survival factor of the infarcted heart

• Published in: Circulation. Heart failure Vol. 3; no. 3; pp. 440 - 450
• Main Authors: Rysä, Jaana, Tenhunen, Olli, Serpi, Raisa, Soini, Ylermi, Nemer, Mona, Leskinen, Hanna, Ruskoaho, Heikki
• Format: Journal Article
• Language: English
• Published: United States 01.05.2010
• Subjects: Animals; Apoptosis; Disease Models, Animal; GATA4 Transcription Factor - physiology; Gene Transfer Techniques; Heart Failure - etiology; Heart Failure - pathology; Heart Failure - prevention & control; Male; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardial Infarction - therapy; Neovascularization, Physiologic - physiology; Rats; Rats, Sprague-Dawley; Ventricular Remodeling - physiology
• ISSN: 1941-3289; 1941-3297
• DOI: 10.1161/CIRCHEARTFAILURE.109.889642

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. 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. 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.