Abstract 723: Cardiomyocyte GATA4 Regulates Angiogenesis in the Adult Mouse Heart
Introduction: GATA4 is a cardiac transcription factor that plays an important role in cardiac embryonic development and the induction and maintenance of postnatal heart growth and cardiomyocyte survival. GATA4 is also required for cardiac functional compensation with age and following hemodynamic stress in vivo. However, the underlying mechanisms whereby GATA4 regulates cardiac cell survival and ability to functionally compensate remains unknown.
Results: Here we generated cardiac-specific transgenic mice that utilize an inducible tetracycline-regulated α-myosin heavy chain promoter system to determine the gain-of-function effects of GATA4 in the heart. We obtained 5 independent lines of GATA4 inducible transgenic mice (TG). Our analysis was focused on Line 20.8, in which removal of doxycycline from the food at the age of 4 weeks (when no GATA4 overexpression was detectable in TG mice vs. control mice) resulted in robust GATA4 overexpression (3–4-fold) in 12-week old mice. Mice with adult onset GATA4 overexpression developed modest cardiac hypertrophy (heart weight/body weight ratio TG 5.4 ± 0.1 vs. control mice 4.8 ± 0.1, p < 0.01), while echocardio-graphically assessed cardiac function (fractional shortening, TG 38 ± 2% vs. control 40 ± 1%) and cardiac dimensions did not significantly differ. The most striking phenotype associated with GATA4 expression in the adult heart was an increase in myocardial microvessel (MV) density, which was assessed as the ratio of microvessel/cardiomyocyte (CM) in cryosections immunostained for the endothelial cell marker CD31 (MV/CM, TG 1.31 ± 0.04 vs. control 0.67 ± 0.04, p < 0.01). Antithetically, 2-month old cardiac specific GATA4 gene-deleted mice (βCre-GATA4flox/flox, before the development of cardiac dysfunction) showed reduced MV density (MV/CM, βCre-GATA4flox/flox 0.6 ± 0.04 vs. βCre-control: 1 ± 0.1, p < 0.05).
Conclusion: Cardiac myocyte GATA4 expression promotes not only cardiomyocyte growth, but also regulates myocardial angiogenesis.