Inhibition of the Ubiquitin-Proteasome Pathway Induces Differential Heat-Shock Protein Response in Cardiomyocytes and Renders Early Cardiac Protection

Stangl, Karl; Günther, Christoph; Frank, Thomas M; Lorenz, Mario; Meiners, Silke; Röpke, Thorsten; Stelter, Lars; Moobed, M.; Baumann, Gert; Kloetzel, Peter‐Michael; Stangl, Verena

doi:10.1006/bbrc.2002.6476

Cited by 79 publications

(56 citation statements)

References 42 publications

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“…8 For induction of hypertrophy, nonconfluent cells were set serum-free for 24 hours and cultivated in M199 medium in the presence of hypertrophic agonists for 24 or 48 hours, either with 0.1% DMSO as a solvent control or with proteasome inhibitors. Representative data from single preparations are shown.…”

Section: Primary Cardiomyocyte Cell Culturementioning

confidence: 99%

Suppression of Cardiomyocyte Hypertrophy by Inhibition of the Ubiquitin-Proteasome System

et al. 2008

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Abstract-Inhibitors of the proteasome interfere with transcriptional regulation of growth signaling pathways and block cell cycle progression of mitotic cells. As growth signaling pathways are highly conserved between mitotic and postmitotic cells, we hypothesized that proteasome inhibition might also be a valuable approach to interfere with hypertrophic growth of postmitotic cardiomyocytes. To test this hypothesis, we analyzed the effects of proteasome inhibition on hypertrophic growth of neonatal rat cardiomyocytes. Partial inhibition of the proteasome effectively suppressed cardiomyocyte hypertrophy as determined by reduced cell size, inhibition of hypertrophy-mediated induction of RNA and protein synthesis, reduced expression of several hypertrophic marker genes, and diminished transcriptional activation of the BNP promotor. Importantly, suppression of hypertrophic growth was independent of the hypertrophic agonist used. Expressional profiling and subsequent Western blot and kinase assays revealed that proteasome inhibition induced a cellular stress response with reduced expression of conserved growth signaling mediators and impaired G1/S phase transition of cardiomyocytes. In hypertensive Dahl-salt sensitive rats, inhibition of the proteasome with low doses of the FDA approved proteasome inhibitor Velcade significantly reduced hypertrophic heart growth. Our data provide important insight into the suppressive effects of proteasome inhibitors on hypertrophic growth of cardiomyocytes and establish low-dose proteasome inhibition as a new and broad-spectrum approach to interfere with cardiac hypertrophy. Key Words: hypertrophy Ⅲ stress Ⅲ gene expression Ⅲ myocytes Ⅲ molecular biology H ypertrophic growth of postmitotic cardiomyocytes is characterized by quantitative effects on cell size, sarcomeric and constitutive proteins, and by qualitative changes in cardiac gene expression. The signal transduction pathways of hypertrophic growth involve several conserved signaling pathways of mitogenic growth and survival, such as activation of G protein-coupled receptors, receptor tyrosine kinases, phosphoinositol-3-kinase, Akt, and extracellular signal regulated kinase 1/2 (Erk1/2). 1 Activation of cardiac specific signaling mediators, eg, calcineurin, also contributes to the hypertrophic growth response of the heart. 1 Hypertrophic signals are further integrated within the cell and result in enhanced RNA and protein synthesis, and altered cell cycle regulation and hypertrophic gene expression. 2 Thus, cardiac hypertrophy appears to be a specialized form of cellular growth that requires mechanisms normally involved in proliferation control-such as growth-mediating signaling pathways and cell cycle regulation. 2 The ubiquitin-proteasome system is the major pathway for intracellular protein degradation in eukaryotic cells. 3 It tightly controls the level of many key proteins involved in cell cycle control, growth and inflammatory signaling, and transcriptional regulation. 4 -6 Whereas sustained inhibition of the proteasome...

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Section: Primary Cardiomyocyte Cell Culturementioning

confidence: 99%

Suppression of Cardiomyocyte Hypertrophy by Inhibition of the Ubiquitin-Proteasome System

et al. 2008

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“…In both studies, peripheral leukocyte, but not myocardial, proteasome activity was determined, and thus it is not clear if the beneficial effect had any relation to myocardial proteasome. An additional study (204) has shown that preperfusion of isolated hearts with the proteasome inhibitor MG132 improves posthypoxic function of excised isolated papillary muscles. However, this was after a prehypoxic delay of at least 30 min with demonstrable increases in heat shock proteins but no determination of myocardial proteasome activity.…”

Section: Proteasome Dysfunction In Myocardial Ischemiamentioning

confidence: 99%

The ubiquitin-proteasome system in cardiac physiology and pathology

Powell

2006

American Journal of Physiology-Heart and Circulatory Physiology

144

118

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The ubiquitin-proteasome system (UPS) is the major nonlysosomal pathway for intracellular protein degradation, generally requiring a covalent linkage of one or more chains of polyubiquitins to the protein intended for degradation. It has become clear that the UPS plays major roles in regulating many cellular processes, including the cell cycle, immune responses, apoptosis, cell signaling, and protein turnover under normal and pathological conditions, as well as in protein quality control by removal of damaged, oxidized, and/or misfolded proteins. This review will present an overview of the structure, biochemistry, and physiology of the UPS with emphasis on its role in the heart, if known. In addition, evidence will be presented supporting the role of certain muscle-specific ubiquitin protein ligases, key regulatory components of the UPS, in regulation of sarcomere protein turnover and cardiomyocyte size and how this might play a role in induction of the hypertrophic phenotype. Moreover, this review will present the evidence suggesting that proteasomal dysfunction may play a role in cardiac pathologies such as myocardial ischemia, congestive heart failure, and myofilament-related and idiopathic-dilated cardiomyopathies, as well as cardiomyocyte loss in the aging heart. Finally, certain pitfalls of proteasome studies will be described with the intent of providing investigators with enough information to avoid these problems. This review should provide current investigators in the field with an up-to-date analysis of the literature and at the same time provide an impetus for new investigators to enter this important and rapidly changing area of research.

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“…Cardiac myocytes were prepared as described previously. 13 After preplating for 2 hours, the adherent cardiac fibroblasts were cultivated under standard conditions in…”

Section: Cell Culturementioning

confidence: 99%

Downregulation of Matrix Metalloproteinases and Collagens and Suppression of Cardiac Fibrosis by Inhibition of the Proteasome

et al. 2004

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Abstract-Myocardial remodeling is an adaptive response of the myocardium to several forms of stress culminating in cardiac fibrosis, left ventricular dilation, and loss of contractility. The remodeling processes of the extracellular matrix are controlled by matrix metalloproteinases, which are in turn regulated by growth factors and inflammatory cytokines. The inflammatory transcription factor nuclear factor B has been implicated in the transcriptional regulation of several matrix metalloproteinases. Because activation of nuclear factor B in turn is essentially controlled by the ubiquitinproteasome system, we investigated the hypothesis that inhibition of the proteasome may prevent activation of matrix metalloproteinases. We demonstrate here that inhibition of the proteasome in rat cardiac fibroblasts suppressed not only expression of matrix metalloproteinases 2 and 9, but also expression of collagen I␣1, I␣2, and III␣1 as determined by in-gel zymography and real-time reverse transcription-polymerase chain reaction. Moreover, myocardial expression of matrix metalloproteinases and collagens was effectively suppressed by systemic treatment of spontaneously hypertensive rats over 12 weeks with the proteasome inhibitor MG132, which resulted in a marked reduction of cardiac fibrosis (Ϫ38%) compared with control animals. We conclude that inhibition of the ubiquitin-proteasome system may provide a new and attractive tool to interfere with collagen and matrix metalloproteinase expression, and therefore might be of possible use in the therapy of myocardial remodeling.

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Inhibition of the Ubiquitin-Proteasome Pathway Induces Differential Heat-Shock Protein Response in Cardiomyocytes and Renders Early Cardiac Protection

Cited by 79 publications

References 42 publications

Suppression of Cardiomyocyte Hypertrophy by Inhibition of the Ubiquitin-Proteasome System

Suppression of Cardiomyocyte Hypertrophy by Inhibition of the Ubiquitin-Proteasome System

The ubiquitin-proteasome system in cardiac physiology and pathology

Downregulation of Matrix Metalloproteinases and Collagens and Suppression of Cardiac Fibrosis by Inhibition of the Proteasome

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