Inducible Activation of c-Myc in Adult Myocardium In Vivo Provokes Cardiac Myocyte Hypertrophy and Reactivation of DNA Synthesis

Xiao, Guishan; Mao, Songyan; Baumgarten, Georg; Serrano, Jennifer; Jordan, Maria C.; Roos, Kenneth P.; Fishbein, Michael C.; MacLellan, W. Robb

doi:10.1161/hh2401.100742

Cited by 143 publications

(159 citation statements)

References 39 publications

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“…This blocks induction of various ␤-catenin-dependent genes, one of which, c-Myc, is also a positive regulator of cardiac growth (35). We found that ␤-catenin was de-stabilized in the transgenic heart since cytosolic levels of ␤-catenin were significantly reduced in the transgenic compared with wild type (Fig.…”

Section: Resultsmentioning

confidence: 74%

Glycogen Synthase Kinase-3β Regulates Growth, Calcium Homeostasis, and Diastolic Function in the Heart

Michael

Haq

Chen

et al. 2004

Journal of Biological Chemistry

124

106

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Glycogen synthase kinase (GSK) 3␤ is a negative regulator of stress-induced cardiomyocyte hypertrophy. It is not clear, however, if GSK-3␤ plays any role in regulating normal cardiac growth and cardiac function. Herein we report that a transgenic mouse expressing wild type GSK-3␤ in the heart has a dramatic impairment of normal post-natal cardiomyocyte growth as well as markedly abnormal cardiac contractile function. The most striking phenotype, however, is grossly impaired diastolic relaxation, which leads to increased filling pressures of the left ventricle and massive atrial enlargement. This is due to profoundly abnormal calcium handling, leading to an inability to normalize cytosolic [Ca 2؉ ] in diastole. The alterations in calcium handling are due at least in part to direct down-regulation of the sarcoplasmic reticulum calcium ATPase (SERCA2a) by GSK-3␤, acting at the level of the SERCA2 promoter. These studies identify GSK-3␤ as a regulator of normal growth of the heart and are the first of which we are aware, to demonstrate regulation of expression of SERCA2a, a critical determinant of diastolic function, by a cytosolic signaling pathway, the activity of which is dynamically modulated. De-regulation of GSK-3␤ leads to severe systolic and diastolic dysfunction and progressive heart failure. Because down-regulation of SERCA2a plays a central role in the diastolic and systolic dysfunction of patients with heart failure, these findings have potential implications for the therapy of this disorder.

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Section: Resultsmentioning

confidence: 74%

Glycogen Synthase Kinase-3β Regulates Growth, Calcium Homeostasis, and Diastolic Function in the Heart

Michael

Haq

Chen

et al. 2004

Journal of Biological Chemistry

124

106

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“…For example, de novo expression of c-myc in adult cardiomyocytes in vitro or in vivo (inducible system) failed to promote cardiomyocyte cytokinesis. 28,34 Several possibilities may explain the observed limited proliferation potential of adult cardiomyocytes. Mature cardiomyocytes contain highly ordered structures, called sarcomeres, which contain contractile proteins required for force generation.…”

Section: Can Adult Mammalian Cardiomyocytes Proliferate?mentioning

confidence: 99%

Cardiomyocyte Proliferation: A Platform for Mammalian Cardiac Repair

Engel¹

2005

Cell Cycle

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“…Systolic blood pressure (SBP) was measured weekly with a tail-cuff system (11). WT and cPPAR␥ Ϫ/Ϫ mice were assessed by echocardiography before minipump implantation and after a 6-week AngII infusion, as previously described (24). Heart rates were determined during echocardiography (under anesthesia) and during SBP measurements.…”

mentioning

confidence: 99%

Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator–Activated Receptor γ in Cardiac Fibrosis

et al. 2008

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OBJECTIVE— Cardiac fibrosis is an important component of diabetic cardiomyopathy. Peroxisome proliferator–activated receptor γ (PPARγ) ligands repress proinflammatory gene expression, including that of osteopontin, a known contributor to the development of myocardial fibrosis. We thus investigated the hypothesis that PPARγ ligands could attenuate cardiac fibrosis. RESEARCH DESIGN AND METHODS— Wild-type cardiomyocyte- and macrophage-specific PPARγ −/− mice were infused with angiotensin II (AngII) to promote cardiac fibrosis and treated with the PPARγ ligand pioglitazone to determine the roles of cardiomyocyte and macrophage PPARγ in cardiac fibrosis. RESULTS— Cardiomyocyte-specific PPARγ −/− mice (cPPARγ −/− ) developed spontaneous cardiac hypertrophy with increased ventricular osteopontin expression and macrophage content, which were exacerbated by AngII infusion. Pioglitazone attenuated AngII-induced fibrosis, macrophage accumulation, and osteopontin expression in both wild-type and cPPARγ −/− mice but induced hypertrophy in a PPARγ-dependent manner. We pursued two mechanisms to explain the antifibrotic cardiomyocyte-PPARγ–independent effects of pioglitazone: increased adiponectin expression and attenuation of proinflammatory macrophage activity. Adenovirus-expressed adiponectin had no effect on cardiac fibrosis and the PPARγ ligand pioglitazone did not attenuate AngII-induced cardiac fibrosis, osteopontin expression, or macrophage accumulation in monocyte-specific PPARγ −/− mice. CONCLUSIONS— We arrived at the following conclusions: 1 ) both cardiomyocyte-specific PPARγ deficiency and activation promote cardiac hypertrophy, 2 ) both cardiomyocyte and monocyte PPARγ regulate cardiac macrophage infiltration, 3 ) inflammation is a key mediator of AngII-induced cardiac fibrosis, 4 ) macrophage PPARγ activation prevents myocardial macrophage accumulation, and 5 ) PPARγ ligands attenuate AngII-induced cardiac fibrosis by inhibiting myocardial macrophage infiltration. These observations have important implications for potential interventions to prevent cardiac fibrosis.

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Inducible Activation of c-Myc in Adult Myocardium In Vivo Provokes Cardiac Myocyte Hypertrophy and Reactivation of DNA Synthesis

Cited by 143 publications

References 39 publications

Glycogen Synthase Kinase-3β Regulates Growth, Calcium Homeostasis, and Diastolic Function in the Heart

Glycogen Synthase Kinase-3β Regulates Growth, Calcium Homeostasis, and Diastolic Function in the Heart

Cardiomyocyte Proliferation: A Platform for Mammalian Cardiac Repair

Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator–Activated Receptor γ in Cardiac Fibrosis

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