Expression of immediate early genes, GATA‐4, and Nkx‐2.5 in adrenergic‐induced cardiac hypertrophy and during regression in adult mice

Saadane, Nacéra; Alpert, Lesley; Chalifour, Lorraine E.

doi:10.1038/sj.bjp.0702676

Cited by 126 publications

(129 citation statements)

References 60 publications

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“…Interestingly, using cDNA microarrays and RPA experiments, we have identified egr1 as a predominant up-regulated gene in the heart of transgenic animals. Egr1, an immediate response gene (29) acting as a transcription factor modulating cellular growth and differentiation, was shown to be overexpressed in hypertrophied hearts of transgenic mice or after infusion of adrenoreceptor agonists (36). Furthermore, the major role played by egr1 in cardiac remodeling was confirmed further by the demonstration of a blunted catecholamine-induced cardiac hypertrophy response in egr1-deficient mice (37).…”

Section: Discussionmentioning

confidence: 66%

Alteration of Cardiac and Renal Functions in Transgenic Mice Overexpressing Human Mineralocorticoid Receptor

Menuet¹,

Isnard²,

Bichara³

et al. 2001

Journal of Biological Chemistry

109

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The mineralocorticoid receptor (MR), a ligand-dependent transcription factor, mediates aldosterone actions in a large variety of tissues. To explore the functional implication of MR in pathophysiology, transgenic mouse models were generated using the proximal human MR (hMR) promoter to drive expression of hMR in aldosterone target tissues. Tissue-specific analysis of transgene expression in two independent transgenic animal (TG) lines by ribonuclease protection assays revealed that hMR is expressed in all mineralocorticoid-sensitive tissues, most notably in the kidney and the heart. TG exhibit both renal and cardiac abnormalities. Enlarged kidneys were histologically associated with renal tubular dilation and cellular vacuolization whose prevalence increased with aging. Renal clearance studies also disclosed a significant decrease in urinary potassium excretion rate in TG. hMRexpressing animals had normal blood pressure but developed mild dilated cardiomyopathy (increased left ventricle diameters and decreased shortening fraction), which was accompanied by a significant increase in heart rate. Differential gene expression analysis revealed a 2-to 5-fold increase in cardiac expression of atrial natriuretic peptide, serum-and glucocorticoid-induced kinase, and early growth response gene 1 as detected by microarrays; renal serum-and glucocorticoid-induced kinase was also induced significantly. Altogether, TG exhibited specific alteration of renal and cardiac functions, thus providing useful pathophysiological models to gain new insights into the tissue-specific mineralocorticoid signaling pathways.

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Section: Discussionmentioning

confidence: 66%

Alteration of Cardiac and Renal Functions in Transgenic Mice Overexpressing Human Mineralocorticoid Receptor

Menuet¹,

Isnard²,

Bichara³

et al. 2001

Journal of Biological Chemistry

109

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“…Csx/Nkx2-5 itself is also differentially regulated by different stimuli. In response to hypertrophic stimuli such as isoproterenol, phenylephrine, and pressure overload, Csx/Nkx2-5 is upregulated (10,11), whereas it is down-regulated by treatment with doxorubicin (DOX) (12). These results suggest that Csx/ Nkx2-5 has certain roles in the adult heart.…”

mentioning

confidence: 56%

Csx/Nkx2-5 Is Required for Homeostasis and Survival of Cardiac Myocytes in the Adult Heart

Toko¹,

Zhu²,

Takimoto³

et al. 2002

Journal of Biological Chemistry

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Csx/Nkx2-5, which is essential for cardiac development of the embryo, is abundantly expressed in the adult heart. We here examined the role of Csx/Nkx2-5 in the adult heart using two kinds of transgenic mice. Transgenic mice that overexpress a dominant negative mutant of Csx/Nkx2-5 (DN-TG mice) showed degeneration of cardiac myocytes and impairment of cardiac function. Doxorubicin induced more marked cardiac dysfunction in DN-TG mice and less in transgenic mice that overexpress wild type Csx/Nkx2-5 (WT-TG mice) compared with non-transgenic mice. Doxorubicin induced cardiomyocyte apoptosis, and the number of apoptotic cardiomyocytes was high in the order of DN-TG mice, non-transgenic mice, and WT-TG mice. Overexpression of the dominant negative mutant of Csx/Nkx2-5 induced apoptosis in cultured cardiomyocytes, while expression of wild type Csx/Nkx2-5 protected cardiomyocytes from doxorubicin-induced apoptotic death. These results suggest that Csx/Nkx2-5 plays a critical role in maintaining highly differentiated cardiac phenotype and in protecting the heart from stresses including doxorubicin.The cardiac homeobox gene Csx/Nkx2-5 starts to be expressed at embryonic day 7.5 in the heart primordia of mice (1, 2), and targeted disruption of murine Csx/Nkx2-5 results in embryonic lethality (3). Many mutations in human Csx/Nkx2-5 have been reported to cause a variety of congenital heart diseases and atrioventricular conduction delay (4, 5). These observations indicate that Csx/Nkx2-5 plays a critical role in cardiac morphogenesis and contributes to diverse cardiac developmental pathways at the embryonic stage.Knockout experiments have suggested that many genes such as Hand1, myocyte enhancer factor-2, atrial natriuretic peptide (ANP), 1 brain natriuretic peptide (BNP), cardiac ␣-actin, cardiac ankyrin repeat protein (CARP), N-myc, and MSX2 are genetically located downstream of Csx/Nkx2-5 at the embryonic stage (2, 6 -8). Although Csx/Nkx2-5 continues to be expressed in the adult heart (1, 2), the function of Csx/Nkx2-5 in the later stage of development is unknown because of embryonic lethality of null mutant mice (3, 8). In our recently generated transgenic mice that overexpress human Csx/Nkx2-5 (WT-TG mice), mRNA levels of many cardiac genes such as ANP, BNP, CARP, and sarcoplasmic reticulum calcium ATPase 2 (SERCA2) genes were up-regulated (9). These results suggest that Csx/Nkx2-5 regulates expression of cardiac-specific genes also in the adult heart. However, because there was no difference in phenotype between WT-TG and non-transgenic (non-TG) mice (9), the significance of these gene up-regulations remains unknown. Csx/Nkx2-5 itself is also differentially regulated by different stimuli. In response to hypertrophic stimuli such as isoproterenol, phenylephrine, and pressure overload, Csx/Nkx2-5 is upregulated (10, 11), whereas it is down-regulated by treatment with doxorubicin (DOX) (12). These results suggest that Csx/ Nkx2-5 has certain roles in the adult heart. In this study, we generated transgenic mice that over...

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“…Studies have uncovered that several transcription factors, including TBX5, NKX2.5, GATA4, and SALL4, cooperate to direct the cardiac cell lineage commitment and/or morphogenesis through the regulation of proteins characteristic of cardiomyocytes and that mutations in these transcription factors are responsible for many cases of CHD (3)(4)(5)(6)(7). Recent data have also suggested the significant roles of these transcription factors for maintenance of the functional heart in postnatal life as well (8)(9)(10)(11)(12). In the past decade, zebrafish (Danio rerio) has emerged as a valuable model system to study many developmental processes, including heart development, and a number of important insights have been gained from analyses of zebrafish mutants (13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

Zebrafish early cardiac connexin, Cx36.7/Ecx, regulates myofibril orientation and heart morphogenesis by establishing Nkx2.5 expression

Sultana¹,

Nag²,

Hoshijima³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Heart development is a precisely coordinated process of cellular proliferation, migration, differentiation, and integrated morphogenetic interactions, and therefore it is highly susceptible to developmental anomalies such as the congenital heart disease (CHD). One of the major causes of CHD has been shown to be the mutations in key cardiac transcription factors, including nkx2.5. Here, we report the analysis of zebrafish mutant ftk that showed a progressive heart malformation in the later stages of heart morphogenesis. Our analyses revealed that the cardiac muscle maturation and heart morphogenesis in ftk mutants were impaired because of the disorganization of myofibrils. Notably, we found that the expression of nkx2.5 was down-regulated in the ftk heart despite the normal expression of gata4 and tbx5, suggesting a common mechanism for the occurrence of ftk phenotype and CHD. We identified ftk to be a loss-of-function mutation in a connexin gene, cx36.7/early cardiac connexin (ecx), expressed during early heart development. We further showed by a rescue experiment that Nkx2.5 is the downstream mediator of Ecx-mediated signaling. From these results, we propose that the cardiac connexin Ecx and its downstream signaling are crucial for establishing nkx2.5 expression, which in turn promotes unidirectional, parallel alignment of myofibrils and the subsequent proper heart morphogenesis.cardiomyocyte ͉ congenital heart disease ͉ trabeculation ͉ futka ͉ positional cloning N ormal development and function of the heart are indispensable for the survival of vertebrates. Cardiogenesis involves a precisely coordinated process of cellular proliferation, migration, and differentiation, and integrated morphogenetic interactions. Because of the complexity of these embryonic processes, heart development is highly susceptible to developmental anomalies collectively known as congenital heart diseases (CHD). The syndrome threatens the lives of as many as 1% of newborns (1, 2). Studies have uncovered that several transcription factors, including TBX5, NKX2.5, GATA4, and SALL4, cooperate to direct the cardiac cell lineage commitment and/or morphogenesis through the regulation of proteins characteristic of cardiomyocytes and that mutations in these transcription factors are responsible for many cases of CHD (3-7). Recent data have also suggested the significant roles of these transcription factors for maintenance of the functional heart in postnatal life as well (8-12). In the past decade, zebrafish (Danio rerio) has emerged as a valuable model system to study many developmental processes, including heart development, and a number of important insights have been gained from analyses of zebrafish mutants (13)(14)(15)(16)(17). In addition to the early determination and differentiation of heart primordium, zebrafish mutations are also expected to contribute to the clarification of a molecular mechanism that governs myofibrillogenesis and morphogenesis of the heart. The unidirectional alignment of myofibrils is essential for proper functio...

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Expression of immediate early genes, GATA‐4, and Nkx‐2.5 in adrenergic‐induced cardiac hypertrophy and during regression in adult mice

Cited by 126 publications

References 60 publications

Alteration of Cardiac and Renal Functions in Transgenic Mice Overexpressing Human Mineralocorticoid Receptor

Alteration of Cardiac and Renal Functions in Transgenic Mice Overexpressing Human Mineralocorticoid Receptor

Csx/Nkx2-5 Is Required for Homeostasis and Survival of Cardiac Myocytes in the Adult Heart

Zebrafish early cardiac connexin, Cx36.7/Ecx, regulates myofibril orientation and heart morphogenesis by establishing Nkx2.5 expression

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