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Azuajeu F.,Laboratory of Cardiovascular Research
Briefings in Bioinformatics | Year: 2011

Tissue growth and regeneration are fundamental processes underpinning crucial physiological and pathological conditions: ranging from normal blood vessel network development, response to stem cells therapy and cancers. Modelling of such biological phenomena has been addressed through mathematical and algorithmic approaches. The former implements continuous representations based on differential equations. The latter exploit operational descriptions in the form of computing programs to represent and execute the models. Within this area, models that define the cell as the fundamental unit of model development, as well as discrete representations of different model entities, are important to plan in vitro experiments and to generate new testable hypotheses. This article reviews the application of algorithmic discrete models, with a focus on tissue growth and regeneration phenomena in the context of health and disease. The review begins with an overview of basic concepts, problems and approaches of computational discrete models. This will include a discussion of basic assumptions and design principles. An overview of key cell-driven approaches and examples of applications in tissue growth and regeneration is provided. The specification, implementation and analysis of a model are illustrated with a hypothetical example, which mimics the branching and sprouting patterns observed in blood vessel network development. The article concludes with a discussion of current challenges and recommendations. © The Author 2010. Published by Oxford University Press.

Goretti E.,Laboratory of Cardiovascular Research | Rolland-Turner M.,Laboratory of Cardiovascular Research | Leonard F.,Laboratory of Cardiovascular Research | Zhang L.,Laboratory of Cardiovascular Research | And 3 more authors.
Journal of Leukocyte Biology | Year: 2013

The capacity of EPCs to repair injured tissues is limited. The role of miRNAs in EPCs is largely unknown. We tested whether miRNAs may be useful to enhance the regenerative capacity of EPCs. Early EPCs were isolated from human PBMCs, and late EPCs were amplified from enriched human peripheral CD34+ cells. Expression profiles of miRNAs and mRNAs were obtained by microarrays. Among the miRNAs differentially expressed between early and late EPCs, five members of the miR-16 family (miR-15a/-15b/-16/-103/-107) were overexpressed in early EPCs. Web-accessible databases predicted 375 gene targets for these five miRNAs. Among these, two regulators of cell cycle progression (CCND1 and CCNE1) and one associated gene (CDK6) were less expressed in early EPCs. Administration of anti-miR-16 in early EPCs enhanced the expression of these three genes, and administration of premiR- 16 in late EPCs decreased their expression. In early EPCs, antagonism of miR-16 allowed for cell-cycle re-entry, stimulated differentiation, enhanced IL-8 secretion, and promoted the formation of capillary-like structures by HUVECs. In conclusion, miR-16 regulates key biological pathways in EPCs. This may have important implications to enhance the capacity of EPCs to repair injured tissues. © Society for Leukocyte Biology.

Azuaje F.,Laboratory of Cardiovascular Research | Devaux Y.,Laboratory of Cardiovascular Research | Wagner D.R.,Laboratory of Cardiovascular Research | Wagner D.R.,Center Hospitalier
BMC Systems Biology | Year: 2010

Background: The identification of potentially relevant biomarkers and a deeper understanding of molecular mechanisms related to heart failure (HF) development can be enhanced by the implementation of biological network-based analyses. To support these efforts, here we report a global network of protein-protein interactions (PPIs) relevant to HF, which was characterized through integrative bioinformatic analyses of multiple sources of "omic" information.Results: We found that the structural and functional architecture of this PPI network is highly modular. These network modules can be assigned to specialized processes, specific cellular regions and their functional roles tend to partially overlap. Our results suggest that HF biomarkers may be defined as key coordinators of intra- and inter-module communication. Putative biomarkers can, in general, be distinguished as "information traffic" mediators within this network. The top high traffic proteins are encoded by genes that are not highly differentially expressed across HF and non-HF patients. Nevertheless, we present evidence that the integration of expression patterns from high traffic genes may support accurate prediction of HF. We quantitatively demonstrate that intra- and inter-module functional activity may be controlled by a family of transcription factors known to be associated with the prevention of hypertrophy.Conclusion: The systems-driven analysis reported here provides the basis for the identification of potentially novel biomarkers and understanding HF-related mechanisms in a more comprehensive and integrated way. © 2010 Azuaje et al; licensee BioMed Central Ltd.

Devaux Y.,Laboratory of Cardiovascular Research | Vausort M.,Laboratory of Cardiovascular Research | McCann G.P.,University of Leicester | Zangrando J.,Laboratory of Cardiovascular Research | And 7 more authors.
Circulation: Cardiovascular Genetics | Year: 2013

Background-Left ventricular (LV) remodeling after acute myocardial infarction is associated with adverse prognosis. MicroRNAs (miRNAs) regulate the expression of several genes involved in LV remodeling. Our aim was to identify miRNAs associated with LV remodeling after acute myocardial infarction. Methods and Results-We studied 90 patients after first ST-segment-elevation acute myocardial infarction. A derivation cohort consisted of 60 patients characterized by echocardiography predischarge and at 6-month follow-up. Thirty patients characterized by magnetic resonance imaging predischarge and at 4-month follow-up were the validation cohort. Remodeling was defined as an increase in LV end-diastolic volume (ΔEDV>0) between discharge and follow-up. Circulating miRNAs were measured by microarrays and polymerase chain reaction. Using a systems-based approach, we identified several miRNAs potentially involved in LV remodeling. In the derivation cohort, one of these miRNAs, miR-150, was downregulated in patients with remodeling (ΔEDV>0) compared with patients without remodeling (ΔEDV≤0). In the validation cohort, patients with remodeling had 2-fold lower levels of miR-150 than those without (P=0.03). miR-150 outperformed N-terminal pro-brain natriuretic peptide to predict remodeling (area under the receiver-operating characteristic curve of 0.74 and 0.60, respectively). miR-150 reclassified 54% (95% confidence interval, 5-102; P=0.03) of patients misclassified by N-terminal pro-brain natriuretic peptide and 59% (95% confidence interval, 9-108; P=0.02) of patients misclassified by a multiparameter clinical model, including age, sex, and admission levels of troponin I, creatine kinase, and N-terminal pro-brain natriuretic peptide. Conclusions-Low circulating levels of miR-150 are associated with LV remodeling after first ST-segment-elevation acute myocardial infarction. miR-150 has potential as a novel biomarker in this setting. © 2013 American Heart Association, Inc.

Emeus I.,Laboratory of Cardiovascular Research | Bonsquenaud M.,Laboratory of Cardiovascular Research | Lenoir B.,Laboratory of Cardiovascular Research | Devaux Y.,Laboratory of Cardiovascular Research | And 2 more authors.
Journal of Leukocyte Biology | Year: 2015

Increase of blood capillary density at the interface between normal and ischemic tissue after acute Ml reduces infarct size and improves cardiac function. Cardiac injury triggers the production of the matricellular component TSP-1, but its role in angiogenesis is not clear, as both anti- and proangiogenic properties have been reported. It is unknown whether TSP-1 is modulated by other factors released during cardiac injury. Among these, Ado is a well-known promoter of angiogenesis. This study determined whether Ado modulates TSP-1 expression and the implication on angiogenesis. Ado dose dependently increased the production of TSP-1 by human macrophages. With the use of agonists and antagonists of AdoRs, coupled to RNA interference, we observed that this effect is mediated via A2AR and A2BR. The Ado effect was reproduced by cholera toxin (Gs protein activator) and forskolin (adenylate cyclase activator) and blocked by the PKA inhibitor H89. Conditioned medium from Ado-treated macrophages stimulated microvessel outgrowth from aortic ring explants by 400%, and induced vessel formation in matrigel plugs, Microvessel outgrowth and vessel formation were blocked completely by addition of anti-TSP-1 antibodies to conditioned medium. Chronic administration of Ado to rats after Ml maintained long-term expression of TSP-1 in the infarct border zone, and this was associated with enhanced border-zone vascularization. Ado up-regulates TSP-1 production by macrophages, resulting in stimulation of angiogenesis. The mechanism Involves A2AR and A2BR and is mediated through the CAMP/PKA pathway. This information may be important when designing Ado-based therapies of angiogenesis. © Society for Leukocyte Biology.

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