GATA-4 Is an Angiogenic Survival Factor of the Infarcted Heart

Abstract

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. Methods and 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-kitϩ 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. Conclusion-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. (Circ Heart Fail. 2010;3:440-450.)Key Words: myocardial infarction Ⅲ heart failure Ⅲ angiogenesis Ⅲ gene therapy A dverse left ventricular (LV) remodeling after myocardial infarction (MI) is a major cause of heart failure (HF) and death. [1][2][3] The molecular mechanisms of post-MI remodeling process are not fully understood but involve alterations in specific signaling molecules, transcription factors (TFs), and their respective downstream pathways. 3 GATA-4 is a zincfinger TF that functions as a key regulator of numerous cardiac genes, such as atrial natriuretic peptide, B-type natriuretic peptide, ␣-myosin heavy chain, and ␤-myosin heavy chain. 4 GATA-4 is also critical for cardiac development, as homozygous GATA-4 -deficient embryos die within 7 to 10 days post coitum owing to defects in ventral morphogenesis and heart tube formation. 5,6 Studies of alleles that cause partial loss of GATA-4 function and conditional deletion of GATA-4 have demonstrated it necessary also for the later phases of heart development and morphogenesis. [7][8][9] Mutations in the human GATA-4 gene have been identified as genetic causes of congenital heart disease. 10,11 In the adult heart, GATA-4 seems to have a unique dual role, on the 1 hand as a mediator of the hypertrophic response and as a survival factor on the other. GATA-4 is required for cardiomyocyte response to hypertrophic stimuli 12 and has been suggested as a nuclea...

GATA4 regulates Fgf16 to promote heart repair after injury

“…Previous work reported that GATA4 is essential for heart development and postnatal maintenance (Bisping et al, 2006). Overexpression of GATA4 was reported to rescue the injured heart after myocardial infarction (MI) by promoting myocardial angiogenesis, preventing heart remodeling and reducing apoptosis, ultimately leading to reduction of infarct size (Rysa et al, 2010). Here, we used an inducible cardiomyocytespecific gene knockout strategy to generate cardiomyocyte-specific and inducible Gata4 knockout mice.…”

Erythropoietin Prevents Hypoxia-Induced GATA-4 Ubiquitination <i>via</i> Phosphorylation of Serine 105 of GATA-4

“…33) Considering the clinical prevalence and significance of myocardial infarction, GATA-4 activation has been proposed as an important component of the transcriptional response to hypoxia. 22) Indeed, GATA-4 could decrease the rate of apoptosis at an early time point and enhance angiogenesis in the infarcted myocardium.…”

“…22) Indeed, GATA-4 could decrease the rate of apoptosis at an early time point and enhance angiogenesis in the infarcted myocardium. 33) Although EPO is a principle regulator of erythropoiesis, EPO receptors are also expressed by other cell types, and EPO has been shown to protect the myocardium against I/R injury or hypoxia 3) via various signal transduction pathways. 4) In cardiomyocytes, EPO was reported to attenuate apoptosis via the PI3K/AKT and ERK 1/2 pathways.…”

“…As previously mentioned, GATA-4 activity is an essential component of the transcriptional response to hypoxia and regulates the JAK-STAT pathways. 33,47) In the field of cardiovascular research, interest in EPO as a therapeutic rescue against I/R injury and cardiac remodeling after myocardial infarction has been raised. The fact that there is a significant time delay in the production of endogenous EPO following injury provides the rationale for the use of exogenous EPO.…”

Gene Therapy of the Heart through Targeting Non-Cardiac Cells

“…Many studies have used intramyocardial injections of DNA to induce angiogenesis. Delivery of the transcription factor GATA-4 ligated to an adenoviral vector before coronary artery ligation resulted in improved left ventricular function and reduced infarct size (Rysä et al, 2010). This was due to increased angiogenesis, decreased apoptosis, and mobilization of cardiac stem cells in GATA-4 treated hearts.…”