Genomic profiling of the human heart before and after mechanical support with a ventricular assist device reveals alterations in vascular signaling networks

Hall, Jennifer L.; Grindle, Suzanne; Han, Xianlin; Fermin, David; Park, Soon; Chen, Yingjie; Bache, Robert J.; Mariash, Ami; Guan, Zhanjun; Ormaza, Sofia; Thompson, Joshua A.; Graziano, Judith A.; Lazaro, Shireen E. de Sam; Pan, Shanlin; Simari, Robert D.; Miller, Leslie W.

doi:10.1152/physiolgenomics.00004.2004

Cited by 118 publications

(73 citation statements)

References 57 publications

(47 reference statements)

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“…66 This gene set included some of those involved in vascular signaling networks, such as neuropilin-1, FGF9, CXCL12 (SDF-1), and endomucin.…”

Section: Changes In the Gene Expression In The Failing Myocardium Aftmentioning

confidence: 99%

Global Gene Expression Profiling in the Failing Myocardium

Asakura

Kitakaze

2009

Circ J

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Heart failure (HF) is a syndrome that involves multiple cellular mechanisms leading to a common phenotype of reduced ventricular contraction and cardiac chamber dilation. To clarify the mechanisms, a number of microarray analyses of the failing myocardium have been conducted. Gene expression profiles are usually compared between opposing pairs of samples, such as non-failing vs failing hearts, ischemic vs non-ischemic hearts, male vs female failing hearts or atria vs ventricles of failing hearts. Apart from these conventional methods, a different novel approach identified cardiac myosin light chain kinase (MLCK) as a HF-related gene by the comprehensive search for the genes that had an expression level that strongly correlated with the severity of HF; further investigations proved the important role of cardiac MLCK in HF. Moreover, a robust gene expression signature composed of 27 genes was revealed on analysis of 4 independent microarray data sets from the failing myocardium of dilated cardiomyopathy. The authors newly demonstrate 107 HF-related genes that were listed in 2 or more of 7 microarray data sets previously reported. Among these genes, many were observed to be involved in mitochondrial dysfunction and oxidative phosphorylation and 3 extracellular molecules, including periostin, pleiotrophin, and SERPINA3, which might become novel diagnostic and therapeutic targets for HF. These novel strategies warrant the new identification of specific genes that are linked to the pathophysiology of HF. (Circ J 2009; 73: 1568 -1576

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“…66 This gene set included some of those involved in vascular signaling networks, such as neuropilin-1, FGF9, CXCL12 (SDF-1), and endomucin.…”

Section: Changes In the Gene Expression In The Failing Myocardium Aftmentioning

confidence: 99%

Global Gene Expression Profiling in the Failing Myocardium

Asakura

Kitakaze

2009

Circ J

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“…Our siGata4 transgenic mice demonstrate that under normal conditions the depletion of up to 80% of Gata4 does not result in cardiac failure in a morphologically normal developed heart. These results may have high clinical impact, since GATA4 mRNA and protein levels vary by approximately twofold between normal and failing human hearts (Hall et al 2004), and doxorubicin, which is broadly used for cancer treatment, causes cardiotoxic heart failure due to GATA4 depletion in wild-type mice (Aries et al 2004). Of note, in models of pressure overload or exercise stimulation GATA4 depletion of about 70% (Gata4fl/ fl a-Mhc-Cre mice) results in cardiac decompensation and dilatation (Oka et al 2006).…”

Section: Reduction Of Gata4 Expression By 80% Does Not Impair the Funmentioning

confidence: 99%

Transgenic mice expressing small interfering RNA against Gata4 point to a crucial role of Gata4 in the heart and gonads

Thurisch

Liang²,

Sarioglu³

et al. 2009

Journal of Molecular Endocrinology

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Homozygous deficiency of the transcription factor Gata4 in mice causes lethality due to defects in ventral morphogenesis and heart tube formation. There is increasing evidence demonstrating that GATA4 function is also relevant for normal developed organ systems, including the heart and endocrinum. To analyze the implication of Gata4 beyond development, we generated transgenic mice expressing inducible small interfering RNA against Gata4. In longitudinal analysis, efficient suppression of Gata4 mRNA (down to 80% of wild-type levels) and protein expression in the heart was detected 38 days after induction of Gata4 short hairpin RNA. Decreased Gata4 expression was associated with reduction in the expression of known cardiac target genes, but the function of the heart remained unperturbed at 20-30% of normal Gata4 levels. Interestingly, Gata4 expression was almost abolished in the ovary and testis. This was accompanied in the testis by a significant reduction of GATA4 downstream target genes, such as the genes encoding Mullerian inhibiting substance (MIS) and steroidogenic acute regulatory (StAR) protein. By contrast, expression levels of Mis and Star were only slightly modified in the ovary, and concentrations of circulating FSH and LH were normal in female transgenic mice after induction of Gata4 short hairpin RNA. However, inhibition of Gata4 expression led to the formation of ovarian teratoma in 10% of females. Histology of the teratomas showed predominantly ectodermal and mesodermal structures. Our data demonstrate that Gata4 is critically involved in the function and integrity of the gonads in vivo.

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“…When examined with this point in mind, the convergent and divergent findings in the two studies, summarized in Table 4, which is published as supporting information on the PNAS web site, suggest that Gata4 is permissive but not dose-limiting for some processes and permissive and dose-limiting for others. In human heart failure, Gata4 mRNA and protein levels vary by Ϸ2-fold between normal and failing human hearts (33,34). Thus, processes in which Gata4 is dose-limiting within the range interrogated by the G4D model are those most likely to be altered downstream of Gata4 in human heart failure.…”

Section: Importance Of Gata4 Gene Dosage In Cardiomyocyte Survival Andmentioning

confidence: 99%

Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure

Bisping

Ikeda

Kong

et al. 2006

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

170

149

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An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiomyocytes, the transcription factor Gata4 is required for agonist-induced hypertrophy. We hypothesized that, in the intact organism, Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed up-regulation of genes associated with apoptosis and fibrosis, including members of the TGF-␤ pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure.apoptosis ͉ hypertrophy ͉ fibrosis ͉ gene expression ͉ Igf-1 H eart failure is one of the leading causes of morbidity and mortality in industrialized countries (1). An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy (2). This is characterized by increased cardiomyocyte size, increased protein synthesis, and altered gene expression. Over time, the changes in gene expression can be maladaptive and contribute to progression of heart failure (3).A large body of evidence suggests that the transcription factor Gata4 is an important regulator of cardiomyocyte hypertrophy (4, 5). Gata4 has been implicated in the regulation of an array of cardiac genes in response to hypertrophic agonists, including atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), skeletal ␣-actin, ␣-myosin heavy chain (␣-MHC), and ␤-myosin heavy chain (␤-MHC) (4, 5). Gata4 overexpression is sufficient to induce the hypertrophic response in cultured neonatal cardiomyocytes and transgenic mice (6). Moreover, the hypertrophic response of cultured neonatal rat cardiomyocytes requires Gata4 (6, 7).We sought to investigate the in vivo role of Gata4 in regulating postnatal heart function and the response to hypertrophic stress. Traditional loss-of-function approaches have been complicated by early embryonic lethality in Gata4 null embryos (8, 9). In our hands, embryos with embryonic cardiac-restricted Gata4 inactivation also suffered from fetal demise (10). These embryos died from heart failure, and the mutant hearts were characterized by marked myocardial hypoplasia due to decreased ca...

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Genomic profiling of the human heart before and after mechanical support with a ventricular assist device reveals alterations in vascular signaling networks

Cited by 118 publications

References 57 publications

Global Gene Expression Profiling in the Failing Myocardium

Global Gene Expression Profiling in the Failing Myocardium

Transgenic mice expressing small interfering RNA against Gata4 point to a crucial role of Gata4 in the heart and gonads

Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure

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