Kinases as therapeutic targets for heart failure

Vlahos, Chris J.; McDowell, Susan A.; Clerk, Angela

doi:10.1038/nrd1009

Cited by 107 publications

(78 citation statements)

References 154 publications

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“…This hypothesis is supported by our observation that even though the persons with emphysema have abstained from smoking for months, their pulmonary p-ERK activity is significantly higher than that of active smokers without the disease. In addition, these data demonstrate that cigarette smoke activates MMP-1 in the absence of a complete inflammatory program, as shown by our epithelial culture system, providing further support for chronic obstructive pulmonary disease research efforts targeted at not only proteolytic enzymes, but also the internal signaling pathways of cells of the lung (47,48).…”

Section: Discussionmentioning

confidence: 76%

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Mercer

Kolesnikova

Sonett

et al. 2004

Journal of Biological Chemistry

158

172

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The interstitial collagenase matrix metalloproteinase-1 (MMP-1) is up-regulated in the lung during pulmonary emphysema. The mechanisms underlying this aberrant expression are poorly understood. Although cigarette smoking is the predominant cause of emphysema, only 15-20% of smokers develop the disease. To define the signaling pathways activated by smoke and to identify molecules responsible for emphysema-associated MMP-1 expression, we performed several in vitro and in vivo experiments. In this study, we showed that cigarette smoke directly induced MMP-1 mRNA and protein expression and increased the collagenolytic activity of human airway cells. Treatment with various chemical kinase inhibitors revealed that this response was dependent on the extracellular regulated kinase-1/2 (ERK) mitogen activated protein kinase pathway. Cigarette smoke increased phosphorylation of residues Thr-202 and Tyr-204 of ERK in airway lining cells and alveolar macrophages in mice at 10 days and 6 months of exposure. Moreover, analysis of lung tissues from emphysema patients revealed significantly increased ERK activity compared with lungs of control subjects. This ERK activity was evident in airway lining and alveolar cells. The identification of active ERK in the lungs of emphysema patients and the finding that induction of MMP-1 by cigarette smoke in pulmonary epithelial cells is ERKdependent reveal a molecular mechanism and potential therapeutic target for excessive matrix remodeling in smokers who develop emphysema.

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Section: Discussionmentioning

confidence: 76%

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Mercer

Kolesnikova

Sonett

et al. 2004

Journal of Biological Chemistry

158

172

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“…Individual PKC isozymes have been implicated in various aspects of cellular physiology involving biological processes as diverse as cell proliferation and differentiation, apoptosis, ion channel regulation, glycogenolysis, and protein secretion (2,3). Moreover, different PKCs have been implicated as potential targets for therapeutic intervention in various diseases including several types of cancer and heart failure (4,5).…”

mentioning

confidence: 99%

Proteome-wide Identification of Cellular Targets Affected by Bisindolylmaleimide-type Protein Kinase C Inhibitors

Brehmer

Godl

Zech

et al. 2004

Molecular & Cellular Proteomics

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Bisindolylmaleimide compounds such as GF109203X are potent inhibitors of protein kinase C (PKC) activity. Although bisindolylmaleimides are not entirely selective for PKC and are known to inhibit a few other protein kinases, these reagents have been extensively used to study the functional roles of PKC family enzymes in cellular signal transduction for more than a decade. Here, we establish a proteomics approach to gain further insights into the cellular effects of this compound class. Functional immobilization of suitable bisindolylmaleimide analogues in combination with the specific purification of cellular binding proteins by affinity chromatography led to the identification of several known and previously unknown enzyme targets. Subsequent in vitro binding and activity assays confirmed the protein kinases Ste20-related kinase and cyclin-dependent kinase 2 (CDK2) and the non-protein kinases adenosine kinase and quinone reductase type 2 as novel targets of bisindolylmaleimide inhibitors. As observed specifically for CDK2, minor chemical variation of the ligand by immobilizing the closely related bisindolylmaleimides III, VIII, and X dramatically affected target binding. These observed changes in affinity correlated with both the measured IC 50 values for in vitro CDK2 inhibition and results from molecular docking into the CDK2 crystal structure. Moreover, the conditions for affinity purification could be adapted in a way that immobilized bisindolylmaleimide III selectively interacted with either PKC␣ or ribosomal S6 protein kinase 1 only after activation of these kinases. Thus, we have established an efficient technique for the rapid identification of cellular bisindolylmaleimide targets and further demonstrate the comparative selectivity profiling of closely related kinase inhibitors within a cellular proteome. Molecular & Cellular Proteomics 3:490 -500, 2004.

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“…However, adult cardiomyocytes are terminally differentiated primary cells and are therefore difficult to work with owing to their short duration of viability. Although neonatal myocytes are not truly representative of the adult phenotype, these cells are usually cultured at confluence allowing for formation of cellcell contacts, which provide crucial survival signals (Vlahos et al 2003). Considering that our study was performed in neonatal cardiomyocyte cultures, it is possible that, depending on the model used, TH may have different effects on the mechanisms investigated in this study.…”

Section: Discussionmentioning

confidence: 84%

New insight into the mechanisms associated with the rapid effect of T3 on AT1R expression

Diniz

Takano²,

Bruneto³

et al. 2012

Journal of Molecular Endocrinology

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The angiotensin II type 1 receptor (AT1R) is involved in the development of cardiac hypertrophy promoted by thyroid hormone. Recently, we demonstrated that triiodothyronine (T 3 ) rapidly increases AT1R mRNA and protein levels in cardiomyocyte cultures. However, the molecular mechanisms responsible for these rapid events are not yet known. In this study, we investigated the T 3 effect on AT1R mRNA polyadenylation in cultured cardiomyocytes as well as on the expression of microRNA-350 (miR-350), which targets AT1R mRNA. The transcriptional and translational actions mediated by T 3 on AT1R levels were also assessed. The total content of ubiquitinated proteins in cardiomyocytes treated with T 3 was investigated. Our data confirmed that T 3 rapidly raised AT1R mRNA and protein levels, as assessed by realtime PCR and western blotting respectively. The use of inhibitors of mRNA and protein synthesis prevented the rapid increase in AT1R protein levels mediated by T 3 . In addition, T 3 rapidly increased the poly-A tail length of the AT1R mRNA, as determined by rapid amplification of cDNA ends poly-A test, and decreased the content of ubiquitinated proteins in cardiomyocytes. On the other hand, T 3 treatment increased miR-350 expression. In parallel with its transcriptional and translational effects on the AT1R, T 3 exerted a rapid posttranscriptional action on AT1R mRNA polyadenylation, which might be contributing to increase transcript stability, as well as on translational efficiency, resulting to the rapid increase in AT1R mRNA expression and protein levels. Finally, these results show, for the first time, that T 3 rapidly triggers distinct mechanisms, which might contribute to the regulation of AT1R levels in cardiomyocytes.

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Kinases as therapeutic targets for heart failure

Cited by 107 publications

References 154 publications

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Proteome-wide Identification of Cellular Targets Affected by Bisindolylmaleimide-type Protein Kinase C Inhibitors

New insight into the mechanisms associated with the rapid effect of T3 on AT1R expression

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