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1.
Data Brief ; 3: 117-9, 2015 Jun.
Article in English | MEDLINE | ID: mdl-26217730

ABSTRACT

This data article is related to the research article entitled Proteomics of Tissue Factor silencing in cardiomyocytic cells reveals a new role for this coagulation factor in splicing machinery control by Lento et al. [1]. Tissue Factor (TF) is a key player in the coagulation cascade, but it has additional functions ranging from angiogenesis, tumour invasion and, in the heart, the maintenance of the integrity of cardiac cells. This article reports the nano-LC-MS(E) analysis of the cardiomyocytic HL-1 cell line proteome and describes the results obtained from a Gene Ontology analysis of those proteins affected by TF-gene silencing.

2.
Vascul Pharmacol ; 67-69: 38-47, 2015.
Article in English | MEDLINE | ID: mdl-25849951

ABSTRACT

BACKGROUND: The long pentraxin PTX3 is an acute-phase multi-functional protein that might play both positive and detrimental effects under different pathophysiological conditions. We previously showed that statins down-regulate the release of PTX3 in human endothelial cells (ECs). The present study investigated the mechanism mediating this effect, its occurrence in other cells involved in atherogenesis, and whether it takes place in experimental atherosclerosis. METHODS AND RESULTS: We found that atorvastatin (1-5 µmol/L) decreased the production and release of PTX3 in human ECs through a post-transcriptional effect. Co-incubation with mevalonate or geranylgeranyl pyrophosphate prevented this effect. Direct blockade of geranylgeranyl transferase I by GGTI-286, treatment with the Rac inhibitor NSC23766 or silencing of the geranylgeranylated GTPase Rac2 by siRNA closely mimicked the action of atorvastatin. In contrast, inactivation of other geranylgeranylated proteins such as RhoA, RhoB, and RhoC or Rac1 did not affect PTX3 release. In addition, we found that atorvastatin also decreased PTX3 secretion in aortic SMCs through a mechanism likely dependent on protein geranylgeranylation, while no effect was observed in monocytes. Finally, we found that atherosclerotic lesions from cholesterol-fed rabbits treated with atorvastatin (2.5 mg/kg/day for 8 weeks) showed less immunoreactive PTX3 than lesions from control animals. CONCLUSIONS: Results suggest that statins may interfere with PTX3 expression in vascular cells via inhibition of protein geranylgeranylation. Since PTX3 is increasingly regarded as an important mediator of the inflammatory response underlying atherosclerosis and its complications, these results highlight the need for further studies of the role of PTX3 and its potential pharmacological modulation in cardiovascular disease.


Subject(s)
Atorvastatin/pharmacology , C-Reactive Protein/biosynthesis , Endothelial Cells/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Protein Prenylation/physiology , Serum Amyloid P-Component/biosynthesis , Animals , C-Reactive Protein/antagonists & inhibitors , Cells, Cultured , Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Protein Prenylation/drug effects , Rabbits , Serum Amyloid P-Component/antagonists & inhibitors
3.
J Proteomics ; 119: 75-89, 2015 Apr 24.
Article in English | MEDLINE | ID: mdl-25668326

ABSTRACT

It has long been known that Tissue Factor (TF) plays a role in blood coagulation and has a direct thrombotic action that is closely related to cardiovascular risk, but it is becoming increasingly clear that it has a much wider range of biological functions that range from inflammation to immunity. It is also involved in maintaining heart haemostasis and structure, and the observation that it is down-regulated in the myocardium of patients with dilated cardiomyopathy suggests that it influences cell-to-cell contact stability and contractility, and thus contributes to cardiac dysfunction. However, the molecular mechanisms underlying these coagulation-independent functions have not yet been fully elucidated. In order to analyse the influence of TF on the cardiomyocitic proteome, we used functional biochemical approaches incorporating label-free quantitative proteomics and gene silencing, and found that this provided a powerful means of identifying a new role for TF in regulating splicing machinery together with the expression of several proteins of the spliceosome, and mRNA metabolism with a considerable impact on cell viability. BIOLOGICAL SIGNIFICANCE: In this study, using quantitative proteomics and functional biochemical approaches, we define for the first time that, in addition to its primary role in blood coagulation, Tissue Factor also plays a novel role in regulating cell splicing machinery, with a relevant impact on cell survival. This new function may help to explain the wide range of biological activities of TF, and thus provide fruitful clues for developing new strategies for treating human diseases in which TF is dysregulated.


Subject(s)
Cardiomyopathy, Dilated/metabolism , Gene Silencing , Myocytes, Cardiac/metabolism , RNA Splicing , Thromboplastin/biosynthesis , Cardiomyopathy, Dilated/pathology , Cell Line, Tumor , Humans , Myocytes, Cardiac/pathology , Proteomics
5.
J Proteomics ; 78: 346-61, 2013 Jan 14.
Article in English | MEDLINE | ID: mdl-23085226

ABSTRACT

The clinical benefits of 3-hydroxy-3-methyl-3-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are closely related to their cholesterol-lowering properties. However, the inhibition of HMG-CoA reductase may also lead to pleiotropic effects due to the ability to inhibit the synthesis of non-steroidal isoprenoid compounds, thus exerting extra-beneficial effect in preventing atherosclerosis beyond their effect on the lipid profile. To identify new drug targets by means of which statins can promote some of their beneficial effects we used a global proteomic approach to analyse the secretome of endothelial cells, a major class of proteins that control a multitude of biological and physiological processes. Differentially expressed proteins were identified using a data-independent, label-free, mass spectrometry-based method. A total of 273 proteins were identified, including 112 that were differentially expressed: 29 uniquely expressed in control cells, 14 uniquely expressed in statin-treated cells, 51 down-regulated by statin, and 18 up-regulated by statin. Gene ontology analysis revealed modulated biological processes related to proteolysis, cellular component organisation and biogenesis, and response to stress. The findings were validated by biochemical assays, thus confirming the effectiveness of our proteomic approach. In conclusion, this study underlines the role of proteomics for the discovery of novel and unpredictable targets of statins.


Subject(s)
Gene Expression Regulation/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Proteome/metabolism , Proteomics , Human Umbilical Vein Endothelial Cells/cytology , Humans , Hybridomas , Proteolysis/drug effects , Stress, Physiological/drug effects
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