Les peptides mimétiques de la Thiorédoxine-1 : nouvelle stratégie thérapeutique pour les maladies cardiovasculaires

Oxidative stress and inflammation play a pathogenic role in atherosclerosis. Thioredoxin-1 (Trx-1) is an anti-oxidative, anti-inflammatory protein with atheroprotective effects. However, in vivo cleavage of Trx-1 generates a truncated pro-inflammatory protein, Trx-80, which compromises the therapeutic use of Trx-1. The aim of my thesis is to characterize a new therapeutic strategy based on Trx-mimetic peptides (TxMP) for the treatment of atherosclerosis. We synthesized a small peptide based on the active site of Trx-1 named CB3. Firstly, CB3 was validated on cultured peritoneal murine macrophages (cellular viability, anti-oxidant and anti-inflammatory responses). Secondly, the atherosclerotic mouse model (ApoE2.Ki) fed a high fat diet was intraperitoneally injected with CB3 to measure their anti-oxidant, anti-inflammatory and anti-atherogenic effects. Our results clearly showed that, similar to the full length Trx-1, CB3 exerts protective effects by reducing inflammation and oxidative stress in macrophages and in ApoE.Ki mice. The atheroprotective effect of CB3 opens promising therapeutic approaches for treatment of atherosclerosis.Le stress oxydatif et l'inflammation jouent un rôle pathogène dans l'athérosclérose. La Thiorédoxine-1 (Trx-1) est une protéine anti-oxydante et anti-inflammatoire ayant des effets athéroprotecteurs. Cependant, le clivage in vivo de la Trx-1 génère une protéine tronquée pro-inflammatoire, la Trx-80, qui compromet l'utilisation thérapeutique de la Trx-1. L'objectif de ma thèse est de caractériser une nouvelle stratégie thérapeutique basée sur l’utilisation des peptides mimétiques de la Trx-1 (TxMP) pour le traitement de l'athérosclérose. Nous avons synthétisé un petit peptide basé sur le site actif de la Trx-1 appelé CB3. D’une part, le peptide CB3 a été validé sur des macrophages murins péritonéaux en culture (viabilité cellulaire, réponses anti-oxydantes et anti-inflammatoires). D’une autre part, un modèle de souris athérosclérotique (ApoE2.Ki) nourri avec un régime alimentaire riche en graisse a reçu une injection de CB3 par voie intrapéritonéale afin de mesurer son effet antioxydant, anti-inflammatoire et anti-athérogène. Nos résultats ont clairement montré que le peptide CB3 exerce des effets protecteurs similaires à la Trx-1, à savoir une réduction de l'inflammation et du stress oxydatif chez les macrophages et les souris ApoE.Ki. L'effet athéroprotecteur du CB3 ouvre des perspectives thérapeutiques prometteuses pour le traitement de l'athérosclérose

Thioredoxin-mimetic peptides : new promising therapeutic strategy for cardiovascular diseases

Le stress oxydatif et l'inflammation jouent un rôle pathogène dans l'athérosclérose. La Thiorédoxine-1 (Trx-1) est une protéine anti-oxydante et anti-inflammatoire ayant des effets athéroprotecteurs. Cependant, le clivage in vivo de la Trx-1 génère une protéine tronquée pro-inflammatoire, la Trx-80, qui compromet l'utilisation thérapeutique de la Trx-1. L'objectif de ma thèse est de caractériser une nouvelle stratégie thérapeutique basée sur l’utilisation des peptides mimétiques de la Trx-1 (TxMP) pour le traitement de l'athérosclérose. Nous avons synthétisé un petit peptide basé sur le site actif de la Trx-1 appelé CB3. D’une part, le peptide CB3 a été validé sur des macrophages murins péritonéaux en culture (viabilité cellulaire, réponses anti-oxydantes et anti-inflammatoires). D’une autre part, un modèle de souris athérosclérotique (ApoE2.Ki) nourri avec un régime alimentaire riche en graisse a reçu une injection de CB3 par voie intrapéritonéale afin de mesurer son effet antioxydant, anti-inflammatoire et anti-athérogène. Nos résultats ont clairement montré que le peptide CB3 exerce des effets protecteurs similaires à la Trx-1, à savoir une réduction de l'inflammation et du stress oxydatif chez les macrophages et les souris ApoE.Ki. L'effet athéroprotecteur du CB3 ouvre des perspectives thérapeutiques prometteuses pour le traitement de l'athérosclérose.Oxidative stress and inflammation play a pathogenic role in atherosclerosis. Thioredoxin-1 (Trx-1) is an anti-oxidative, anti-inflammatory protein with atheroprotective effects. However, in vivo cleavage of Trx-1 generates a truncated pro-inflammatory protein, Trx-80, which compromises the therapeutic use of Trx-1. The aim of my thesis is to characterize a new therapeutic strategy based on Trx-mimetic peptides (TxMP) for the treatment of atherosclerosis. We synthesized a small peptide based on the active site of Trx-1 named CB3. Firstly, CB3 was validated on cultured peritoneal murine macrophages (cellular viability, anti-oxidant and anti-inflammatory responses). Secondly, the atherosclerotic mouse model (ApoE2.Ki) fed a high fat diet was intraperitoneally injected with CB3 to measure their anti-oxidant, anti-inflammatory and anti-atherogenic effects. Our results clearly showed that, similar to the full length Trx-1, CB3 exerts protective effects by reducing inflammation and oxidative stress in macrophages and in ApoE.Ki mice. The atheroprotective effect of CB3 opens promising therapeutic approaches for treatment of atherosclerosis

A thioredoxin-mimetic peptide exerts potent anti-inflammatory, antioxidant, and atheroprotective effects in ApoE2.Ki mice fed high fat diet

International audienceTime for primary review: 40 days Aims Oxidative stress and inflammation play a pathogenic role in atherosclerosis. Thioredoxin-1 (Trx-1) is an antioxidative, anti-inflammatory protein with atheroprotective effects. However, in vivo cleavage of Trx-1 generates a truncated pro-inflammatory protein, Trx-80, which compromises the therapeutic use of Trx-1. Here we analysed whether the thioredoxin-mimetic peptide (TxMP), CB3 might exert anti-oxidative, anti-inflammatory, and atheroprotective effects in ApoE2.Ki mice

A thioredoxin-mimetic peptide exerts potent anti-inflammatory, antioxidant, and atheroprotective effects in ApoE2.Ki mice fed high fat diet

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Soluble CD89 is a critical factor for mesangial proliferation in childhood IgA nephropathy

International audienceChildhood IgA nephropathy (IgAN) includes a wide spectrum of clinical presentations, from isolated hematuria to acute nephritis with rapid loss of kidney function. In adults, IgAN is an autoimmune disease and its pathogenesis involves galactose deficient (Gd) IgA1, IgG anti-Gd-IgA1 autoantibodies and the soluble IgA Fc receptor (CD89). However, implication of such factors, notably soluble CD89, in childhood IgAN pathogenesis remains unclear. Here, we studied these biomarkers in a cohort of 67 patients with childhood IgAN and 42 pediatric controls. While Gd-IgA1 was only moderately increased in patient plasma, levels of circulating IgA complexes (soluble CD89-IgA and IgG-IgA) and free soluble CD89 were markedly increased in childhood IgAN. Soluble CD89-IgA1 complexes and free soluble CD89 correlated with proteinuria, as well as histological markers of disease activity: mesangial, endocapillary hypercellularity and cellular crescents. Soluble CD89 was found in patient's urine but not in urine from pediatric controls. Mesangial deposits of soluble CD89 were detected in biopsies from patients with childhood IgAN. Serum chromatographic fractions containing covalently linked soluble CD89-IgA1 complexes or free soluble CD89 from patients induced mesangial cell proliferation in vitro in a soluble CD89-dependent manner. Recombinant soluble CD89 induced mesangial cell proliferation in vitro which was inhibited by free soluble recombinant CD71 (also a mesangial IgA receptor) or mTOR blockers. Interestingly, injection of recombinant soluble CD89 induced marked glomerular proliferation and proteinuria in mice expressing human IgA1. Thus, free and IgA1-complexed soluble CD89 are key players in mesangial proliferation. Hence, our findings suggest that soluble CD89 plays an essential role in childhood IgAN pathogenesis making it a potential biomarker and therapeutic target

Human Plasma Thioredoxin-80 Increases With Age and in ApoE −/− Mice Induces Inflammation, Angiogenesis, and Atherosclerosis

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