Increased Protein Kinase C Activity in Myotrophin-Induced Myocyte Growth

Sil, Parames C.; Kandaswamy, Vijaya; Sen, Subha

doi:10.1161/01.res.82.11.1173

Cited by 47 publications

(24 citation statements)

References 64 publications

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“…Sections (taken from same areas of the heart of WT and Tg mice) were stained with hematoxylin/eosin for structural analysis using standard techniques, and myocyte dimensions were quantitated by image scanning using the Image Pro Plus software program. (11)-Hearts were taken out from heparininjected mice and were cannulated via aorta (n ϭ 6). Hearts were perfused with perfusion buffer (glucose (1 g), NaHCO 3 (0.58 g), and pyruvic acid (0.27 g), pH 7.3) with 95% O 2 and 5% CO 2 on a Langendorff apparatus.…”

Section: Methodsmentioning

confidence: 99%

Cardiac Overexpression of Myotrophin Triggers Myocardial Hypertrophy and Heart Failure in Transgenic Mice

Sarkar

Leaman

Gupta

et al. 2004

Journal of Biological Chemistry

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Cardiac hypertrophy and heart failure remain leading causes of death in the United States. Many studies have suggested that, under stress, myocardium releases factors triggering protein synthesis and stimulating myocyte growth. We identified and cloned myotrophin, a 12-kDa protein from hypertrophied human and rat hearts. Myotrophin (whose gene is localized on human chromosome 7q33) stimulates myocyte growth and participates in cellular interaction that initiates cardiac hypertrophy in vitro. In this report, we present data on the pathophysiological significance of myotrophin in vivo, showing the effects of overexpression of cardiospecific myotrophin in transgenic mice in which cardiac hypertrophy occurred by 4 weeks of age and progressed to heart failure by 9 -12 months. This hypertrophy was associated with increased expression of proto-oncogenes, hypertrophy marker genes, growth factors, and cytokines, with symptoms that mimicked those of human cardiomyopathy, functionally and morphologically. This model provided a unique opportunity to analyze gene clusters that are differentially upregulated during initiation of hypertrophy versus transition of hypertrophy to heart failure. Importantly, changes in gene expression observed during initiation of hypertrophy were significantly different from those seen during its transition to heart failure. Our data show that overexpression of myotrophin results in initiation of cardiac hypertrophy that progresses to heart failure, similar to changes in human heart failure. Knowledge of the changes that take place as a result of overexpression of myotrophin at both the cellular and molecular levels will suggest novel strategies for treatment to prevent hypertrophy and its progression to heart failure.Cardiac hypertrophy and heart failure remain leading causes of death in the United States. Although the mechanisms are not well understood, previous studies have suggested that, under stress, the myocardium releases factor(s) that trigger protein synthesis and cardiomyocyte growth. In vivo and in vitro studies have shown that many growth factors contribute to the cardiac hypertrophy process (1, 2). Studies from our laboratory and others have demonstrated that factors other than high blood pressure are responsible for initiating cardiac hypertrophy in the setting of hypertension (3, 4). We hypothesized that mechanical or humoral factors act on the myocardium, inducing one or more factors that trigger protein synthesis and myocardial cell growth. Using spontaneously hypertensive rats, we identified and characterized a 12-kDa protein, myotrophin, that stimulates myocyte growth (5). The myotrophin gene was mapped, for the first time, to human chromosome band 7q33 (6). We have shown that myotrophin stimulates transcription of proto-oncogenes (e.g. c-myc, c-fos, and c-jun), (7) ␤-myosin heavy chain (␤-MHC), 1 atrial natriuretic factor (ANF), and connexin (7). Large increases in myotrophin correlate with the onset of hypertrophy in spontaneously hypertensive rats and humans (8).The purpose...

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Section: Methodsmentioning

confidence: 99%

Cardiac Overexpression of Myotrophin Triggers Myocardial Hypertrophy and Heart Failure in Transgenic Mice

Sarkar

Leaman

Gupta

et al. 2004

Journal of Biological Chemistry

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“…Mice Overexpressing Myotrophin-As described previously (28), hearts were taken out from heparin-injected mice and cannulated via aorta (n ϭ 6). Hearts were perfused with perfusion buffer (glucose, 1 g; NaHCO 3 , 0.58 g; and pyruvic acid, 0.27 g, pH 7.3) with 95% O 2 and 5% CO 2 on a Langendorff apparatus.…”

Section: Isolation Of Cardiac Myocytes From Hearts Of Wt and Tgmentioning

confidence: 99%

Myocardial Cell Death and Regeneration during Progression of Cardiac Hypertrophy to Heart Failure

Sarkar¹,

Chawla‐Sarkar²,

Young³

et al. 2004

Journal of Biological Chemistry

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Cardiac hypertrophy and ensuing heart failure are among the most common causes of mortality worldwide, yet the triggering mechanisms for progression of hypertrophy to failure are not fully understood. Tissue homeostasis depends on proper relationships between cell proliferation, differentiation, and death and any imbalance between them results in compromised cardiac function. Recently, we developed a transgenic (Tg) mouse model that overexpress myotrophin (a 12-kDa protein that stimulates myocyte growth) in heart resulting in hypertrophy that progresses to heart failure. This provided us an appropriate model to study the disease process at any point from initiation of hypertrophy end-stage heart failure. We studied detailed apoptotic signaling and regenerative pathways and found that the Tg mouse heart undergoes myocyte loss and regeneration, but only at a late stage (during transition to heart failure). Several apoptotic genes were up-regulated in 9-month-old Tg hearts compared with age-matched wild type or 4-week-old Tg hearts. Cardiac cell death during heart failure involved activation of Fas, tumor necrosis factor-␣, and caspases 9, 8, and 3 and poly(ADP-ribose) polymerase cleavage. Tg mice with hypertrophy associated with compromised functionshowedsignificantup-regulationofcyclins,cyclindependent kinases (Cdks), and cell regeneration markers in myocytes. Furthermore, in human failing and nonfailing hearts, similar observations were documented including induction of active caspase 3 and Ki-67 proteins in dilated cardiomyopathic myocytes. Taken together, our data suggest that the stress of extensive myocardial damage from longstanding hypertrophy may cause myocytes to reenter the cell cycle. We demonstrate, for the first time in an animal model, that cell death and regeneration occur simultaneously in myocytes during end-stage heart failure, a phenomenon not observed at the onset of the disease process.

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“…Primary cultures of neonatal cardiomyocytes were prepared according to the procedure described by Sil et al (1998) [19]. After 4 days of culture, these preparations contained >95% cardiomyocytes.…”

Section: Cardiomyocyte Isolation and In Vitro Experimental Protocolmentioning

confidence: 99%

The protective role of arjunolic acid against doxorubicin induced intracellular ROS dependent JNK-p38 and p53-mediated cardiac apoptosis

et al. 2011

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Increased Protein Kinase C Activity in Myotrophin-Induced Myocyte Growth

Cited by 47 publications

References 64 publications

Cardiac Overexpression of Myotrophin Triggers Myocardial Hypertrophy and Heart Failure in Transgenic Mice

Cardiac Overexpression of Myotrophin Triggers Myocardial Hypertrophy and Heart Failure in Transgenic Mice

Myocardial Cell Death and Regeneration during Progression of Cardiac Hypertrophy to Heart Failure

The protective role of arjunolic acid against doxorubicin induced intracellular ROS dependent JNK-p38 and p53-mediated cardiac apoptosis

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