Cardiomyocyte GATA4 functions as a stress-responsive regulator of angiogenesis in the murine heart

Abstract

During the preparation of the manuscript, an error occurred in the wording of the final sentence of the abstract. The correct sentence appears below.To our knowledge, these results demonstrate a previously unrecognized function for GATA4 as a regulator of cardiac angiogenesis through a nonhypoxic, load, and/or disease-responsive mechanism.The JCI regrets the error.

NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis

“…Previous work shows that a central mechanism underpinning myocardial stress-induced angiogenesis is the release of angiogenic factors, notably VEGF (25)(26)(27). We found that cardiac VEGF-A protein levels were significantly increased in Nox4-transgenic mice whereas Nox4-null mice had markedly lower levels than wild-type after pressure overload (Fig.…”

“…The major mechanism underlying the beneficial effects of Nox4 during load-induced stress is an increase in myocardial capillaries, with capillary density being impaired in Nox4-null animals but better preserved in Nox4-transgenic mice compared with wild type. Myocardial angiogenesis is tightly coupled to cardiomyocyte growth during heart development (34) and is also an important determinant of the response to disease-causing stresses such as pressure overload (24)(25)(26)(27). Stress-induced angiogenesis has been shown to be underpinned by the release of VEGF from cardiomyocytes to exert paracrine effects on adjacent vessels (25).…”

“…Myocardial VEGF production is under the control of transcription factors such as Hif1 and GATA4 (26,27), but the upstream signals regulating activation of these factors during cardiac stress remain unclear. The results reported here suggest that stressinduced increase in Nox4 levels is a key mechanism that enhances cardiomyocyte Hif1α levels during overload, in turn leading to VEGF release and an increase in angiogenic capacity.…”

“…Levels of myocardial apoptosis after pressure overload were also unaffected either by Nox4 deletion or by cardiomyocyte-specific overexpression [WT band: 7.2 ± 1.1; KO band: 6.7 ± 1.1; transgenic band: 6.0 ± 0.9/10 5 nuclei; n = 6-9/group; P = NS]. A key determinant of functional cardiac compensation during chronic pressure overload has recently been recognized as the extent of myocardial capillarization, with insufficient angiogenesis being a driver of heart failure (24)(25)(26)(27). Quantification of myocardial capillary density in LV sections of Nox4-null mice, Nox4-transgenic mice, and respective wild-type littermate controls showed that although there were no differences between groups at baseline, after imposition of pressure overload, capillary density was significantly lower in Nox4-null mice compared with wild type (Fig.…”

Promoting differentiation and survival of human c-kit+ cardiac progenitor cells ex vivo.

“…Also, Gata4 has also been shown to promote cardiac angiogenesis. For instance, conditional overexpression of GATA4 in adult cardiomyocytes increased myocardial capillary formation and increased coronary flow reserve and perfusion-dependent cardiac contractility [48]. These studies suggest that Gata4 activation in CPCs used for heart repair may have multi-faceted benefits, including promoting CPC differentiation and survival, as well as promoting cardiac angiogenesis.…”