Epigenetic Regulation of Adipocytes Phenotype: Implication for Perivascular Adipose Tissue Contribution to Cardiometabolic Diseases

Perivascular adipose tissue (PVAT) has emerged in the past decades as an integral part of the vasculature (tunica adiposa), contributing by the release of adipokines, to important physiological process such as vascular tone regulation. The metabolic syndrome is associated with an increase deposition of PVAT and the development of atherosclerosis. Whereas healthy PVAT protect the vasculature from inflammation, lipid accumulation and hypothermia, the dysfunctional PVAT observed in the metabolic syndrome favour many features of atherosclerosis such as endothelial dysfunction, vascular smooth muscle proliferation and inflammation. The down- and up-regulation of adiponectin, leptin and nerve growth factor, respectively in the dysfunctional PVAT perfectly illustrates this change. Phenotypically, healthy PVAT resembles the thermogenic brown and beige adipocytes, however, recent data suggest a loss of PVAT thermogenic phenotype during the metabolic syndrome in a process called `PVAT whitening`. This review will provide a current perspective on the factors susceptible to influence PVAT epigenetics and the consequences of PVAT dysfunction on cardiometabolic diseases

The TGF-β/Smad Repressor TG-Interacting Factor 1 (TGIF1) Plays a Role in Radiation-Induced Intestinal Injury Independently of a Smad Signaling Pathway

Despite advances in radiation delivery protocols, exposure of normal tissues during the course of radiation therapy remains a limiting factor of cancer treatment. If the canonical TGF-β/Smad pathway has been extensively studied and implicated in the development of radiation damage in various organs, the precise modalities of its activation following radiation exposure remain elusive. In the present study, we hypothesized that TGF-β1 signaling and target genes expression may depend on radiation-induced modifications in Smad transcriptional co-repressors/inhibitors expressions (TGIF1, SnoN, Ski and Smad7). In endothelial cells (HUVECs) and in a model of experimental radiation enteropathy in mice, radiation exposure increases expression of TGF-β/Smad pathway and of its target gene PAI-1, together with the overexpression of Smad co-repressor TGIF1. In mice, TGIF1 deficiency is not associated with changes in the expression of radiation-induced TGF-β pathway-related transcripts following localized small intestinal irradiation. In HUVECs, TGIF1 overexpression or silencing has no influence either on the radiation-induced Smad activation or the Smad3-dependent PAI-1 overexpression. However, TGIF1 genetic deficiency sensitizes mice to radiation-induced intestinal damage after total body or localized small intestinal radiation exposure, demonstrating that TGIF1 plays a role in radiation-induced intestinal injury. In conclusion, the TGF-β/Smad co-repressor TGIF1 plays a role in radiation-induced normal tissue damage by a Smad-independent mechanism

Role of mast cells in radiation proctitis development in vivo and endothelial response to radiation exposure in vitro.

La radiothérapie est utilisée seule ou en association avec la chimiothérapie dans le traitement de plus de 50% des cancers. En dépit des progrès techniques dans la balistique, l'irradiation des tissus sains entourant la tumeur et les effets secondaires qui lui sont associés sont une limite à la dose d'irradiation utilisée. Ces effets secondaires, lorsqu'ils concernent le tube digestif, ont un retentissement important sur la qualité de vie des patients et peuvent même engager leur pronostic vital. La compréhension des mécanismes impliqués dans le développement de ces lésions est donc un enjeu majeur dans l'identification de cibles thérapeutiques permettant leur prévention et leur traitement. Durant ma thèse nous avons étudié le rôle des mastocytes dans le développement de la rectite radique in vivo et dans la réponse endothéliale à l'irradiation in vitro. Nos résultats suggèrent un rôle délétère des mastocytes dans le développement de la rectite radique humaine et murine, notamment par l'influence de certains de leurs médiateurs tels que l'histamine et les protéases sur le phénotype des cellules musculaires lisses de la muscularis propria. Le ciblage de certains médiateurs mastocytaires pourrait représenter une nouvelle stratégie thérapeutique pour prévenir et/ou limiter les atteintes radiques digestives. D'autre part, nos travaux montrent que des médiateurs mastocytaires comme l'histamine peuvent exacerber la réponse inflammatoire de l'endothélium à l'irradiation par des mécanismes de signalisation impliquant l'activation de la voie p38 MAPKinase et du facteur de transcription NF-B. L'étude approfondie des voies de signalisation activées lors du développement des lésions radiques pourrait offrir de nouvelles possibilités thérapeutiques dans la gestion des dommages radiques aux tissus sains.Radiation therapy is used alone or in combination with chemotherapy in more than 50% of cancer treatments. Despite recent advances in treatment delivery such as dose-sculpting techniques, irradiation of healthy tissues surrounding the tumor and the associated side effects limit the radiation amount used. Those side effects when concerning the gastrointestinal tract, have profound repercussions on patient's quality of life and may even engage their vital prognosis. The comprehension of the mechanisms implicated in the development of these lesions is thus a major stake in the identification of therapeutic targets allowing their prevention and treatment. During my PhD, we studied the role of mast cells in the development of radiation proctitis in vivo and in the endothelial response to irradiation in vitro. Our results suggest that mast cells have a deleterious role in the development of human and murine radiation proctitis, in particular by the influence of some of its mediators such as histamine and proteases on the phenotype of the smooth muscle cells of the muscularis propria. Targeting mast cells'mediators may represent new therapeutic tools to prevent and/or limit digestive radiation damage. Other shares our work shows that mast cells mediators such as histamine can exacerbate the endothelial inflammatory response to irradiation by mechanisms involving the activation of the p38MAPKinase pathway and the transcription factor NF-B. The study of intracellular signaling pathways activated during radiation damage development may offer new therapeutic possibilities in the management of healthy tissues radiation damage

Rôle des mastocytes dans le développement de la rectite radique in vivo et la réponse endothéliale à l'irradiation in vitro

La radiothérapie est utilisée seule ou en association avec la chimiothérapie dans le traitement de plus de 50% des cancers. En dépit des progrès techniques dans la balistique, l'irradiation des tissus sains entourant la tumeur et les effets secondaires qui lui sont associés sont une limite à la dose d'irradiation utilisée. Ces effets secondaires, lorsqu'ils concernent le tube digestif, ont un retentissement important sur la qualité de vie des patients et peuvent même engager leur pronostic vital. La compréhension des mécanismes impliqués dans le développement de ces lésions est donc un enjeu majeur dans l'identification de cibles thérapeutiques permettant leur prévention et leur traitement. Durant ma thèse nous avons étudié le rôle des mastocytes dans le développement de la rectite radique in vivo et dans la réponse endothéliale à l'irradiation in vitro. Nos résultats suggèrent un rôle délétère des mastocytes dans le développement de la rectite radique humaine et murine, notamment par l'influence de certains de leurs médiateurs tels que l'histamine et les protéases sur le phénotype des cellules musculaires lisses de la muscularis propria. Le ciblage de certains médiateurs mastocytaires pourrait représenter une nouvelle stratégie thérapeutique pour prévenir et/ou limiter les atteintes radiques digestives. D'autre part, nos travaux montrent que des médiateurs mastocytaires comme l'histamine peuvent exacerber la réponse inflammatoire de l'endothélium à l'irradiation par des mécanismes de signalisation impliquant l'activation de la voie p38 MAPKinase et du facteur de transcription NF- B. L'étude approfondie des voies de signalisation activées lors du développement des lésions radiques pourrait offrir de nouvelles possibilités thérapeutiques dans la gestion des dommages radiques aux tissus sains.Radiation therapy is used alone or in combination with chemotherapy in more than 50% of cancer treatments. Despite recent advances in treatment delivery such as dose-sculpting techniques, irradiation of healthy tissues surrounding the tumor and the associated side effects limit the radiation amount used. Those side effects when concerning the gastrointestinal tract, have profound repercussions on patient's quality of life and may even engage their vital prognosis. The comprehension of the mechanisms implicated in the development of these lesions is thus a major stake in the identification of therapeutic targets allowing their prevention and treatment. During my PhD, we studied the role of mast cells in the development of radiation proctitis in vivo and in the endothelial response to irradiation in vitro. Our results suggest that mast cells have a deleterious role in the development of human and murine radiation proctitis, in particular by the influence of some of its mediators such as histamine and proteases on the phenotype of the smooth muscle cells of the muscularis propria. Targeting mast cells'mediators may represent new therapeutic tools to prevent and/or limit digestive radiation damage. Other shares our work shows that mast cells mediators such as histamine can exacerbate the endothelial inflammatory response to irradiation by mechanisms involving the activation of the p38MAPKinase pathway and the transcription factor NF- B. The study of intracellular signaling pathways activated during radiation damage development may offer new therapeutic possibilities in the management of healthy tissues radiation damage.PARIS-EST-Université (770839901) / SudocPARIS12-Bib. électronique (940280011) / SudocSudocFranceF

Rôle des mastocytes dans le développement de la rectite radique in vivo et de la réponse endothéliale à l'irradiation in vitro

Radiation therapy is used alone or in combination with chemotherapy in more than 50% of cancer treatments. Despite recent advances in treatment delivery such as dose-sculpting techniques, irradiation of healthy tissues surrounding the tumor and the associated side effects limit the radiation amount used. Those side effects when concerning the gastrointestinal tract, have profound repercussions on patient's quality of life and may even engage their vital prognosis. The comprehension of the mechanisms implicated in the development of these lesions is thus a major stake in the identification of therapeutic targets allowing their prevention and treatment. During my PhD, we studied the role of mast cells in the development of radiation proctitis in vivo and in the endothelial response to irradiation in vitro. Our results suggest that mast cells have a deleterious role in the development of human and murine radiation proctitis, in particular by the influence of some of its mediators such as histamine and proteases on the phenotype of the smooth muscle cells of the muscularis propria. Targeting mast cells'mediators may represent new therapeutic tools to prevent and/or limit digestive radiation damage. Other shares our work shows that mast cells mediators such as histamine can exacerbate the endothelial inflammatory response to irradiation by mechanisms involving the activation of the p38MAPKinase pathway and the transcription factor NF-B. The study of intracellular signaling pathways activated during radiation damage development may offer new therapeutic possibilities in the management of healthy tissues radiation damage.La radiothérapie est utilisée seule ou en association avec la chimiothérapie dans le traitement de plus de 50% des cancers. En dépit des progrès techniques dans la balistique, l'irradiation des tissus sains entourant la tumeur et les effets secondaires qui lui sont associés sont une limite à la dose d'irradiation utilisée. Ces effets secondaires, lorsqu'ils concernent le tube digestif, ont un retentissement important sur la qualité de vie des patients et peuvent même engager leur pronostic vital. La compréhension des mécanismes impliqués dans le développement de ces lésions est donc un enjeu majeur dans l'identification de cibles thérapeutiques permettant leur prévention et leur traitement. Durant ma thèse nous avons étudié le rôle des mastocytes dans le développement de la rectite radique in vivo et dans la réponse endothéliale à l'irradiation in vitro. Nos résultats suggèrent un rôle délétère des mastocytes dans le développement de la rectite radique humaine et murine, notamment par l'influence de certains de leurs médiateurs tels que l'histamine et les protéases sur le phénotype des cellules musculaires lisses de la muscularis propria. Le ciblage de certains médiateurs mastocytaires pourrait représenter une nouvelle stratégie thérapeutique pour prévenir et/ou limiter les atteintes radiques digestives. D'autre part, nos travaux montrent que des médiateurs mastocytaires comme l'histamine peuvent exacerber la réponse inflammatoire de l'endothélium à l'irradiation par des mécanismes de signalisation impliquant l'activation de la voie p38 MAPKinase et du facteur de transcription NF-B. L'étude approfondie des voies de signalisation activées lors du développement des lésions radiques pourrait offrir de nouvelles possibilités thérapeutiques dans la gestion des dommages radiques aux tissus sains

Mast cells in colo-rectal damage following radiation exposure

Radiation therapy, alone or in combination with chemotherapy and/or surgery, is used in more than half of cancer treatments and contributes to increased number of cancer survivors. However radiation exposure is associated with toxicity in non malignant tissues, and represents a strong limitation in the use of this therapeutic tool. The intestine is on of the most radio-sensitive organ and may be comprised in the irradiation field in most of the treatment schedules for pelvic cancers such as prostatic tumors. The irradiated healthy colorectum appears inflamed and is accompanied by acute pain and bleeding in 80% of patients. For 5 to 10% of them, chronic tissue fibrosis may lead to organ dysfunction and require surgical resection. Mast cells hyperplasia has been observed in many fibrotic disorders comprising renal failure, asthma, liver cirrhosis and Crohns disease. The ability of mast cells to liberate a wild range of neutral protease, cytokines and fibrogenic mediators, together with their localisation closed to the endothelium, mucosa and nervous system make them putative key regulators of the response of the different tissue compartments to radiation exposure. Human tissues were obtained from surgical resections 6 weeks post-radiotherapy for rectal adenocarcinoma. Radiation damage, and especially vascular dystrophy, was associated with mast cell hyperplasia, as revealed by tryptase and c-kit immunostaining, both mast cell specific antigens. To evaluate the exact role of mast cells in inflammatory and fibrotic injury following radiation exposure, we used a model of mouse radiation rectocolitis induced by a localized single dose exposure of 27Gy. Radiation injury is characterized by acute apoptosis in the stem cell compartment (1 and 3 days), strong inflammatory reaction with mucosal ulcerations (14 days) and progressive tissue fibrosis until 14 weeks post-exposure. These observations are consistent with tissue damage observed in human rectal radiation injury. At the molecular level, mRNA analysis revealed increased expression of two mast cell proteases: mouse chymase and mouse carboxypeptidase A-3, with respective maximum increases of 9.7 and 2.7 fold. Moreover, relative PAI-1 expression, a fibrogenic mediator known to be secreted by activated mast cells, was up-regulated from day 1 to 14 weeks post irradiation. These preliminary data confirm the interest to study the role of mast cells in radiation enteropathy. Studies on ongoing to compare molecular and histological changes induced by radiation exposure in mast cell deficient mice versus congenic wild type mice to elucidate mast cell implication in radiation enteritis and fibrosis

The stellate vascular smooth muscle cell phenotype is induced by IL-1β via the secretion of PGE2 and subsequent cAMP-dependent protein kinase A activation

International audienceAtherosclerosis development is associated with morphological changes to intimal cells, leading to a stellate cell phenotype. In this study, we aimed to determine whether and how key pro-atherogenic cytokines present in atherosclerotic plaques (IL-1β, TNFα and IFNγ) could induce this phenotype, as these molecules are known to trigger the transdifferentiation of vascular smooth muscle cells (VSMCs). We found that, IL-1β was the only major inflammatory mediator tested capable of inducing a stellate morphology in VSMCs. This finding was confirmed by staining for F-actin and vinculin at focal adhesions, as these two markers were disrupted only by IL-1β. We then investigated the possible association of this IL-1β-dependent change in morphology with an increase in intracellular cAMP concentration ([cAMP]), using the FRET-based biosensor for cAMP TEpacVV. Experiments in the presence of IL-1β or medium conditioned by IL-1β-treated VSMCs and pharmacological tools demonstrated that the long-term increase in intracellular cAMP concentration was induced by the secretion of an autocrine/paracrine mediator, prostaglandin E2 (PGE2), acting through the EP4 receptor. Finally, by knocking down the expression of the regulatory subunit PKAR1α, thereby reproducing the effects of IL-1β and PGE2 on VSMCs, we demonstrated the contribution of PKA activity to the observed behavior of VSMCs

Radiothérapie : quelles orientations thérapeutiques contre les séquelles digestives ?

Malgré les progrès constants des techniques d’imagerie et de ciblage tumoral et la qualité des protocoles de radiothérapie, le traitement des tumeurs pelviennes entraîne inévitablement des dommages aux tissus sains digestifs. L’entérite radique aiguë concerne 80 % des patients. L’atteinte des cellules souches responsables du renouvellement épithélial compromet les capacités régénératrices de la muqueuse, et le développement d’un processus inflammatoire provoque des dystrophies et des ulcérations. Dans 5 à 10 % des cas, l’évolution des dommages aigus est défavorable, et les patients développent des lésions chroniques caractérisées par un processus cicatriciel exagéré, une fibrose voire une nécrose de la paroi digestive. Les recherches précliniques et cliniques ont permis de mettre en évidence des orientations thérapeutiques nouvelles basées sur la régénération muqueuse, la réduction de l’activation du compartiment vasculaire et de son rôle dans l’inflammation et la thrombose, enfin la lutte contre l’activation chronique des cellules du mésenchyme. Les pistes sont prometteuses et de multiples stratégies se sont avérées efficaces sur des modèles précliniques. De nombreux efforts restent cependant à fournir pour parvenir au but que partagent les biologistes et les radiothérapeutes, à savoir la protection des tissus sains lors de l’application des protocoles anticancéreux

Mast cells and ionizing radiation induce a synergistic expression of inflammatory genes in endothelial cells by a Mechanism involving p38α MAP Kinase and (p65) NF-κB activation

International audienceVascular endothelium is a key compartment involved in the development of normal tissue toxicity associated with cancer radiation therapy, i.e., acute inflammation and late fibrosis. Radiation-induced endothelial cell activation has been extensively studied, and activated endothelial cells are characterized by increased expression of inflammatory mediators and adhesion molecules, and activation of the coagulation and thrombosis pathways. However, little is known about the role of vascular endothelium interaction with resident immune cells, such as mast cells on its response to irradiation. Here, we report that endothelial exposure to mast cell conditioned medium and irradiation induces a synergistic expression of many inflammatory genes including interleukin-6 and interleukin-8, CXCL2 and E-selectin. This synergy is blocked by the histamine H1 receptor antagonist mepyramine and partially mimicked by exogenous histamine addition before irradiation. Using pharmacological and molecular inhibition approaches, we show the p38a MAP kinase and p65 (NF-κB) dependence of the synergy. Moreover, our data show a link between both pathways, with p65 (NF-κB) being downstream of p38. These data highlight the possible exacerbation of the radiation-induced endothelial inflammatory response by its interactions with immune cells. It also suggest that p38α MAP kinase and p65 (NF-κB) inhibition in vascular endothelium may limit excessive tissue inflammation induced by radiation therapy, and thereby limit the associated acute and late tissue damage. © 2012 by Radiation Research Society