Src and Multiple MAP Kinase Activation in Cardiac Hypertrophy and Congestive Heart Failure Under Chronic Pressure-overload: Comparison with Acute Mechanical Stretch

Takeishi, Yasuchika; Huang, Qunhua; Abe, Jun; Glassman, Michael; Che, Wenyi; Lee, Jiing Dwan; Kawakatsu, Hisaaki; Lawrence, Earl; Hoit, Brian D.; Berk, Bradford C.; Walsh, Richard A.

doi:10.1006/jmcc.2001.1427

Cited by 134 publications

(109 citation statements)

References 18 publications

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“…We found that Erk5 activity was increased by pressure overload (Fig. 8, which is published as supporting information on the PNAS web site), in agreement with previously reported pressure overload models (21,22). However, Erk5 pathway activation was not different between G4D and WT mice (Fig.…”

Section: Gata4 Regulation Of Cardiomyocyte Hypertrophy Based On In Vsupporting

confidence: 91%

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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Section: Gata4 Regulation Of Cardiomyocyte Hypertrophy Based On In Vsupporting

confidence: 91%

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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“…Although PKC was known to be present in cardiac cells and to translocate in response to Gq-coupled GPCR agonists (61), no cardiac-related phenotype had been reported in PKCdeficient mice in the absence of agonist challenge (33). It is worth noting that PKC deficiency does not alter the levels of the other PKC isotypes in different tissues (33), thus making unlikely that changes in such PKC isoforms (11) may underlie the observed effects on G␣ q signaling.…”

Section: Discussionmentioning

confidence: 99%

“…(MEF2A and C) of ERK5 induce cardiac hypertrophy in mice (23,26), and that the activity of ERK5 is increased during left ventricular hypertrophy (24,61), whereas targeted deletion of ERK5 attenuates the hypertrophic response in the heart (25). It is also worth noting that high levels of the antiapoptotic protein Bcl2 have been found in early stages of hypertrophy (67) and that arterial wall thickness, perivascular fibrosis, and cardiac hypertrophy induced by angiotensin II treatment are significantly reduced in Ets-1-deficient mice (68).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C (PKC)ζ-mediated Gαq Stimulation of ERK5 Protein Pathway in Cardiomyocytes and Cardiac Fibroblasts

García-Hoz

Sánchez-Fernández

García‐Escudero

et al. 2012

Journal of Biological Chemistry

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Background: We have recently described that G␣ q acts as an adaptor protein that facilitates PKC-mediated activation of ERK5. Results: Our results show that PKC is essential for Gq-dependent ERK5 activation in cardiomyocytes and cardiac fibroblasts. Conclusion: This novel signaling axis plays a key role in cardiac hypertrophy programs. Significance: The G␣ q /PKC/ERK5 pathway would be active in such pathological settings, providing new therapeutic targets.

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“…Several points in the Ang II signal transduction pathways are possible sites of STS action (Force and Bonventre, 1998;Miyazaki et al, 1998;Dostal and Baker, 1999). Although the mechanism by which AngII induces cardiomyocyte hypertrophy is not fully understood, protein kinases especially the MAPK family have been reported to play a pivotal role in the development of cardiac hypertrophy (Kim et al, 1999;Seko et al, 1999;Fischer et al, 2001;Takeishi et al, 2001). Among the MAPK superfamily, ERK1/2 has been focused on the essential regulators of a hypertrophic response although the role of JNK and p38 were recently studied in regulating cardiac hypertrophy (Sugden, 2001).…”

Section: Discussionmentioning

confidence: 99%

Sodium tanshinone IIA sulfonate depresses angiotensin II-induced cardiomyocyte hypertrophy through MEK/ERK pathway

Liu

Zou²,

Liang³

et al. 2007

Exp Mol Med

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Cardiomyocyte hypertrophy is a major cause of morbidity and mortality worldwide. The aim of this study is to determine the effects of sodium tanshinone IIA sulfonate (STS) on cardiomyocyte hypertrophy induced by angiotensin II (Ang II) in vivo and in vitro. In long-term treatment, adult Wistar rats were infused with Ang II for three weeks via osmotic mini-pumps and some of them were given intragastrically of STS. Left ventricle was isolated; the ratio of left ventricular weight to body weight and systolic blood pressure (SBP) were determined and heart morphometry was assessed after hematoxylin and eosin staining. Results indicated STS inhibited Ang II-induced increases in myocyte diameter and decreased the LVW/BW ratio independent of decreasing systolic blood pressure. In vitro, treatment of cultured cardiomyocytes with STS inhibited Ang II-induced increase in cell size, protein synthesis, ANP expression, activation of extracellular signalregulated kinase (ERK) and ERK kinase (MEK). Then we reexamined the mechanism of STS-induced antihypertrophic effects. Results revealed MEK inhibitor U0126 (20 µM) markedly enhanced STS-induced depressions in [ 3 H]leucine incorporation and ANP expression. In conclusion, MEK/ERK pathway plays a significant role in the anti-hypertrophic effects of STS.

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Src and Multiple MAP Kinase Activation in Cardiac Hypertrophy and Congestive Heart Failure Under Chronic Pressure-overload: Comparison with Acute Mechanical Stretch

Cited by 134 publications

References 18 publications

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

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

Protein Kinase C (PKC)ζ-mediated Gαq Stimulation of ERK5 Protein Pathway in Cardiomyocytes and Cardiac Fibroblasts

Sodium tanshinone IIA sulfonate depresses angiotensin II-induced cardiomyocyte hypertrophy through MEK/ERK pathway

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