Microarray Analyses of Inflammation Response of Human Dermal Fibroblasts to Different Strains of Borrelia burgdorferi Sensu Stricto

In Lyme borreliosis, the skin is the key site of bacterial inoculation by the infected tick, and of cutaneous manifestations, erythema migrans and acrodermatitis chronica atrophicans. We explored the role of fibroblasts, the resident cells of the dermis, in the development of the disease. Using microarray experiments, we compared the inflammation of fibroblasts induced by three strains of Borrelia burgdorferi sensu stricto isolated from different environments and stages of Lyme disease: N40 (tick), Pbre (erythema migrans) and 1408 (acrodermatitis chronica atrophicans). The three strains exhibited a similar profile of inflammation with strong induction of chemokines (CXCL1 and IL-8) and IL-6 cytokine mainly involved in the chemoattraction of immune cells. Molecules such as TNF-alpha and NF-κB factors, metalloproteinases (MMP-1, -3 and -12) and superoxide dismutase (SOD2), also described in inflammatory and cellular events, were up-regulated. In addition, we showed that tick salivary gland extracts induce a cytotoxic effect on fibroblasts and that OspC, essential in the transmission of Borrelia to the vertebrate host, was not responsible for the secretion of inflammatory molecules by fibroblasts. Tick saliva components could facilitate the early transmission of the disease to the site of injury creating a feeding pit. Later in the development of the disease, Borrelia would intensively multiply in the skin and further disseminate to distant organs

Transcriptomic and Lipidomic Mapping of Macrophages in the Hub of Chronic Beta-Adrenergic-Stimulation Unravels Hypertrophy-, Proliferation-, and Lipid Metabolism-Related Genes as Novel Potential Markers of Early Hypertrophy or Heart Failure

Sympathetic nervous system overdrive with chronic release of catecholamines is the most important neurohormonal mechanism activated to maintain cardiac output in response to heart stress. Beta-adrenergic signaling behaves first as a compensatory pathway improving cardiac contractility and maladaptive remodeling but becomes dysfunctional leading to pathological hypertrophy and heart failure (HF). Cardiac remodeling is a complex inflammatory syndrome where macrophages play a determinant role. This study aimed at characterizing the temporal transcriptomic evolution of cardiac macrophages in mice subjected to beta-adrenergic-stimulation using RNA sequencing. Owing to a comprehensive bibliographic analysis and complementary lipidomic experiments, this study deciphers typical gene profiles in early compensated hypertrophy (ECH) versus late dilated remodeling related to HF. We uncover cardiac hypertrophy- and proliferation-related transcription programs typical of ECH or HF macrophages and identify lipid metabolism-associated and Na+ or K+ channel-related genes as markers of ECH and HF macrophages, respectively. In addition, our results substantiate the key time-dependent role of inflammatory, metabolic, and functional gene regulation in macrophages during beta-adrenergic dependent remodeling. This study provides important and novel knowledge to better understand the prevalent key role of resident macrophages in response to chronically activated beta-adrenergic signaling, an effective diagnostic and therapeutic target in failing hearts

Rôle de PRG-1, une phospholipide phosphatase neuronale, dans la régulation de la migration et de la prolifération des cellules musculaires lisses vasculaires

Le remodelage vasculaire, caractéristique des pathologies cardiovasculaires, correspond à la modulation phénotypique des cellules musculaires lisses (CML). L acide lysophosphatidique (LPA) en est un puissant inducteur, qui active la dédifférenciation, la migration et la prolifération des CML et induit une formation néointimale. Des études sur la média aortique remodelée ont montré une diminution de l expression de PRG-1 (Plasticity Related Gene-1) qui appartient à la superfamille des Lipides Phosphatases/phosphoTransférases (LPT), enzymes catalysant la dégradation des phospholipides par déphosphorylation. Le but de ce travail est de comprendre le rôle de PRG-1 dans la régulation des effets connus du LPA dans le vaisseau. L expression de PRG-1 a été confirmée, en ARN et en protéine, dans la média aortique murine et humaine. Cette expression est diminuée au cours de la modulation phénotypique des CML en culture in vitro, et in vivo dans des coupes de vaisseaux humains et murins présentant une hyperplasie néointimale. La surexpression de PRG-1, par infection adénovirale des CML, inhibe la prolifération et la migration induites par le LPA in vitro. In vivo, les vaisseaux surexprimant PRG-1 présentent une forte diminution de la resténose post-angioplastie par ballonnet. Enfin, la phosphorylation de p42/p44, induite par le LPA, est atténuée en présence de PRG-1. Ce travail montre l expression de PRG-1 au niveau vasculaire et son rôle dans l inhibition des effets pro-prolifératifs et pro-migratoires du LPA sur les CML in vitro et in vivo. Nous avons donc mis en évidence, une nouvelle protéine qui joue un rôle protecteur en conditions physiopathologiques vasculaires.PARIS-BIUP (751062107) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Early Protective Role of Inflammation in Cardiac Remodeling and Heart Failure: Focus on TNFα and Resident Macrophages

International audienceCardiac hypertrophy, initiated by a variety of physiological or pathological stimuli (hemodynamic or hormonal stimulation or infarction), is a critical early adaptive compensatory response of the heart. The structural basis of the progression from compensated hypertrophy to pathological hypertrophy and heart failure is still largely unknown. In most cases, early activation of an inflammatory program reflects a reparative or protective response to other primary injurious processes. Later on, regardless of the underlying etiology, heart failure is always associated with both local and systemic activation of inflammatory signaling cascades. Cardiac macrophages are nodal regulators of inflammation. Resident macrophages mostly attenuate cardiac injury by secreting cytoprotective factors (cytokines, chemokines, and growth factors), scavenging damaged cells or mitochondrial debris, and regulating cardiac conduction, angiogenesis, lymphangiogenesis, and fibrosis. In contrast, excessive recruitment of monocyte-derived inflammatory macrophages largely contributes to the transition to heart failure. The current review examines the ambivalent role of inflammation (mainly TNFα-related) and cardiac macrophages (Mφ) in pathophysiologies from non-infarction origin, focusing on the protective signaling processes. Our objective is to illustrate how harnessing this knowledge could pave the way for innovative therapeutics in patients with heart failure

Aspects moléculaires de l’expression et de la régulation de la synthase endothéliale du monoxyde d’azote

L’isoforme endothéliale de la synthase du monoxyde d’azote (eNOS) assure la production enzymatique de monoxyde d’azote (NO) dans les cellules endothéliales et dans d’autres types cellulaires, tels que les neurones, les plaquettes et plusieurs types de cellules épithéliales. Le rôle physiologique de la eNOS a été bien défini dans plusieurs types cellulaires, comme la relaxation des cellules musculaires lisses vasculaires et la potentialisation à long terme dans certains neurones, en particulier grâce à des expériences d’inactivation génique. Bien qu’exprimée constitutivement dans les cellules endothéliales, la eNOS subit des régulations par des facteurs physiques, biochimiques et hormonaux, agissant au niveau transcriptionnel ou post-transcriptionnel. Plusieurs éléments fonctionnels de régulation transcriptionnelle ont été mis en évidence dans le promoteur de la eNOS, qui sont actifs dans les cellules endothéliales et non endothéliales, et nous présentons des éléments démontrant que ces éléments ne suffisent pas à expliquer l’expression à un niveau élevé de la eNOS dans les cellules endothéliales

Le projet Jurismart : une recherche interdisciplinaire sur les réseaux énergétiques intelligents

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Acetylation of TAF(I)68, a subunit of TIF-IB/SL1, activates RNA polymerase I transcription

Mammalian rRNA genes are preceded by a terminator element that is recognized by the transcription termination factor TTF-I. In exploring the functional significance of the promoter-proximal terminator, we found that TTF-I associates with the p300/CBP-associated factor PCAF, suggesting that TTF-I may target histone acetyltransferase to the rDNA promoter. We demonstrate that PCAF acetylates TAF(I)68, the second largest subunit of the TATA box-binding protein (TBP)-containing factor TIF-IB/SL1, and acetylation enhances binding of TAF(I)68 to the rDNA promoter. Moreover, PCAF stimulates RNA polymerase I (Pol I) transcription in a reconstituted in vitro system. Consistent with acetylation of TIF-IB/SL1 being required for rDNA transcription, the NAD(+)-dependent histone deacetylase mSir2a deacetyl ates TAF(I)68 and represses Pol I transcription. The results demonstrate that acetylation of the basal Pol I transcription machinery has functional consequences and suggest that reversible acetylation of TIF-IB/SL1 may be an effective means to regulate rDNA transcription in response to external signals

Gene Structure, Polymorphism and Mapping of the Human Endothelial Nitric Oxide Synthase Gene

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Characterization of an Upstream Enhancer Region in the Promoter of the Human Endothelial Nitric-oxide Synthase Gene

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Progenitor/Stem Cells in Vascular Remodeling during Pulmonary Arterial Hypertension

International audiencePulmonary arterial hypertension (PAH) is characterized by an important occlusive vascular remodeling with the production of new endothelial cells, smooth muscle cells, myofibroblasts, and fibroblasts. Identifying the cellular processes leading to vascular proliferation and dysfunction is a major goal in order to decipher the mechanisms leading to PAH development. In addition to in situ proliferation of vascular cells, studies from the past 20 years have unveiled the role of circulating and resident vascular in pulmonary vascular remodeling. This review aims at summarizing the current knowledge on the different progenitor and stem cells that have been shown to participate in pulmonary vascular lesions and on the pathways regulating their recruitment during PAH. Finally, this review also addresses the therapeutic potential of circulating endothelial progenitor cells and mesenchymal stem cells