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1. Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice

Author

Mouna Chajadine, Ludivine Laurans, Tobias Radecke, Nirmala Mouttoulingam, Rida Al-Rifai, Emilie Bacquer, Clara Delaroque, Héloïse Rytter, Marius Bredon, Camille Knosp, José Vilar, Coralie Fontaine, Nadine Suffee, Marie Vandestienne, Bruno Esposito, Julien Dairou, Jean Marie Launay, Jacques Callebert, Alain Tedgui, Hafid Ait-Oufella, Harry Sokol, Benoit Chassaing, and Soraya Taleb

Subjects
Science
Abstract

Abstract Tryptophan (Trp) is an essential amino acid, whose metabolism is a key gatekeeper of intestinal homeostasis. Yet, its systemic effects, particularly on atherosclerosis, remain unknown. Here we show that high-fat diet (HFD) increases the activity of intestinal indoleamine 2, 3-dioxygenase 1 (IDO), which shifts Trp metabolism from the production of microbiota-derived indole metabolites towards kynurenine production. Under HFD, the specific deletion of IDO in intestinal epithelial cells leads to intestinal inflammation, impaired intestinal barrier, augmented lesional T lymphocytes and atherosclerosis. This is associated with an increase in serotonin production and a decrease in indole metabolites, thus hijacking Trp for the serotonin pathway. Inhibition of intestinal serotonin production or supplementation with indole derivatives alleviates plaque inflammation and atherosclerosis. In summary, we uncover a pivotal role of intestinal IDO in the fine-tuning of Trp metabolism with systemic effects on atherosclerosis, paving the way for new therapeutic strategies to relieve gut-associated inflammatory diseases.

Published
2024
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2. Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy

Author

Yujiao Zhang, Marie Vandestienne, Jean-Rémi Lavillegrand, Jeremie Joffre, Icia Santos-Zas, Aonghus Lavelle, Xiaodan Zhong, Wilfried Le Goff, Maryse Guérin, Rida Al-Rifai, Ludivine Laurans, Patrick Bruneval, Coralie Guérin, Marc Diedisheim, Melanie Migaud, Anne Puel, Fanny Lanternier, Jean-Laurent Casanova, Clément Cochain, Alma Zernecke, Antoine-Emmanuel Saliba, Michal Mokry, Jean-Sebastien Silvestre, Alain Tedgui, Ziad Mallat, Soraya Taleb, Olivia Lenoir, Cécile Vindis, Stéphane M. Camus, Harry Sokol, and Hafid Ait-Oufella

Subjects
Science
Abstract

Abstract Caspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe -/- mice as well as hematopoietic deletion in Ldlr -/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe -/- Rag2 -/- Card9 -/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1β production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.

Published
2023
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3. JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm

Author

Rida Al-Rifai, Marie Vandestienne, Jean-Rémi Lavillegrand, Tristan Mirault, Julie Cornebise, Johanne Poisson, Ludivine Laurans, Bruno Esposito, Chloé James, Olivier Mansier, Pierre Hirsch, Fabrizia Favale, Rayan Braik, Camille Knosp, Jose Vilar, Giuseppe Rizzo, Alma Zernecke, Antoine-Emmanuel Saliba, Alain Tedgui, Maxime Lacroix, Lionel Arrive, Ziad Mallat, Soraya Taleb, Marc Diedisheim, Clément Cochain, Pierre-Emmanuel Rautou, and Hafid Ait-Oufella

Subjects
Science
Abstract

JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development remains unknown. Here, the authors show that JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.

Published
2022
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4. Soluble TREM-1 plasma levels are associated with acute kidney injury, acute atrial fibrillation and prolonged ICU stay after cardiac surgery- a proof-concept study

Author

Marie Vandestienne, Rayan Braik, Jean-Rémi Lavillegrand, Geoffroy Hariri, Zoe Demailly, Nadine Ben Hamouda, Fabienne Tamion, Thomas Clavier, and Hafid Ait-Oufella

Subjects
cardiopulmonary bypass, cytokine, TREM-1, inflammation, outcome, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

BackgroundCardiopulmonary bypass (CPB) during cardiac surgery leads to deleterious systemic inflammation. We hypothesized that TREM-1, a myeloid receptor shed after activation, drives systemic inflammation during CPB.MethodsProspective observational bi-centric study. Blood analysis (flow cytometry and ELISA) before and at H2 and H24 after CPB. Inclusion of adult patients who underwent elective cardiac surgery with CPB.ResultsTREM-1 expression on neutrophils decreased between H0 and H2 while soluble (s)TREM-1 plasma levels increased. sTREM-1 levels increased at H2 and at H24 (p

Published
2023
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5. Cytotoxic CD8+ T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling

Author

Icia Santos-Zas, Jeremie Lemarié, Ivana Zlatanova, Marine Cachanado, Jean-Christophe Seghezzi, Hakim Benamer, Pascal Goube, Marie Vandestienne, Raphael Cohen, Maya Ezzo, Vincent Duval, Yujiao Zhang, Jin-Bo Su, Alain Bizé, Lucien Sambin, Philippe Bonnin, Maxime Branchereau, Christophe Heymes, Corinne Tanchot, José Vilar, Clement Delacroix, Jean-Sebastien Hulot, Clement Cochain, Patrick Bruneval, Nicolas Danchin, Alain Tedgui, Ziad Mallat, Tabassome Simon, Bijan Ghaleh, Jean-Sébastien Silvestre, and Hafid Ait-Oufella

Subjects
Science
Abstract

Immune cells contribute to adverse remodeling following myocardial infarction. Here the authors show in mice and pigs that CD8+ lymphocytes release Granzyme B in the infarcted heart leading to cardiomyocyte death, enhanced inflammation and deterioration of cardiac function.

Published
2021
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6. Author Correction: JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm

Author

Rida Al-Rifai, Marie Vandestienne, Jean-Rémi Lavillegrand, Tristan Mirault, Julie Cornebise, Johanne Poisson, Ludivine Laurans, Bruno Esposito, Chloé James, Olivier Mansier, Pierre Hirsch, Fabrizia Favale, Rayan Braik, Camille Knosp, Jose Vilar, Giuseppe Rizzo, Alma Zernecke, Antoine-Emmanuel Saliba, Alain Tedgui, Maxime Lacroix, Lionel Arrive, Ziad Mallat, Soraya Taleb, Marc Diedisheim, Clément Cochain, Pierre-Emmanuel Rautou, and Hafid Ait-Oufella

Subjects
Science
Published
2022
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7. Indoleamine 2 3-dioxygenase knockout limits angiotensin II-induced aneurysm in low density lipoprotein receptor-deficient mice fed with high fat diet.

Author

Sarvenaz Metghalchi, Marie Vandestienne, Yacine Haddad, Bruno Esposito, Julien Dairou, Alain Tedgui, Ziad Mallat, Stephane Potteaux, and Soraya Taleb

Subjects
Medicine, Science
Abstract

AIMS:Abdominal aortic aneurysm (AAA) is an age-associated disease characterized by chronic inflammation, vascular cell apoptosis and metalloproteinase-mediated extracellular matrix degradation. Despite considerable progress in identifying targets involved in these processes, therapeutic approaches aiming to reduce aneurysm growth and rupture are still scarce. Indoleamine 2-3 dioxygenase 1 (IDO) is the first and rate-limiting enzyme involved in the conversion of tryptophan (Trp) into kynurenine (Kyn) pathway. In this study, we investigated the role of IDO in two different models of AAA in mice. METHODS AND RESULTS:Mice with deficiencies in both low density receptor-deficient (Ldlr-/-) and IDO (Ldlr-/-Ido1-/-) were generated by cross-breeding Ido1-/- mice with Ldlr-/-mice. To induce aneurysm, these mice were infused with angiotensin II (Ang II) (1000 ng/min/kg) and fed with high fat diet (HFD) during 28 days. AAAs were present in almost all Ldlr-/- infused with AngII, but only in 50% of Ldlr-/-Ido1-/- mice. Immunohistochemistry at an early time point (day 7) revealed no changes in macrophage and T lymphocyte infiltration within the vessel wall, but showed reduced apoptosis, as assessed by TUNEL assay, and increased α-actin staining within the media of Ldlr-/-Ido1-/- mice, suggesting enhanced survival of vascular smooth muscle cells (VSMCs) in the absence of IDO. In another model of elastase-induced AAA in C57Bl/6 mice, IDO deficiency had no effect on aneurysm formation. CONCLUSION:Our study showed that the knockout of IDO prevented VSMC apoptosis in AngII -treated Ldlr-/- mice fed with HFD, suggesting a detrimental role of IDO in AAA formation and thus would be an important target for the treatment of aneurysm.

Published
2018
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8. TREM-1 orchestrates angiotensin II–induced monocyte trafficking and promotes experimental abdominal aortic aneurysm

Author

Laurie Soulat-Dufour, Alexandre Boissonnas, Giulia Chinetti, Florence Pinet, Ludivine Laurans, Fabien Lareyre, Andreas Giraud, Léa Guyonnet, Soraya Taleb, Bruno Esposito, Coralie L. Guerin, Marc Derive, Sylvie Lang, Juliette Raffort, José Vilar, Alain Tedgui, Marie Vandestienne, Jean-Sébastien Silvestre, Amir Boufenzer, Hafid Ait-Oufella, Ziad Mallat, Icía Santos-Zas, Rida Al-Rifai, Yujiao Zhang, Patrick Bruneval, Jérémie Joffre, Eric Clauser, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of California [San Francisco] (UC San Francisco), University of California (UC), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), INOTREM SA, Faculté de Médecine [Nancy], Université de Lorraine (UL)-Université de Lorraine (UL), Institut Curie [Paris], Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Luxembourg Institute of Health (LIH), Service de Cardiologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), University of Cambridge [UK] (CAM), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pinet, Florence, Mallat, Ziad [0000-0003-0443-7878], Apollo - University of Cambridge Repository, Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), and ANR-18-CE14-0009,TETRAAA,EXploration et modulation du récépteur TREM-1 dans la maldie anévrysmale aortique(2018)

Subjects
0301 basic medicine, Mice, Knockout, ApoE, Interleukin-1beta, Inflammation, macromolecular substances, Monocytes, Proinflammatory cytokine, Mice, 03 medical and health sciences, Aortic aneurysm, 0302 clinical medicine, Downregulation and upregulation, Cell migration/adhesion, Cell Movement, Vascular Biology, medicine.artery, Animals, Humans, Medicine, Innate immunity, Aorta, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Tumor Necrosis Factor-alpha, business.industry, Angiotensin II, Monocyte, General Medicine, medicine.disease, Triggering Receptor Expressed on Myeloid Cells-1, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, cardiovascular system, Cancer research, Matrix Metalloproteinase 2, Tumor necrosis factor alpha, medicine.symptom, business, Gene Deletion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article, Aortic Aneurysm, Abdominal
Abstract

International audience; The triggering receptor expressed on myeloid cells 1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our objective was to explore the role of TREM-1 in a mouse model of angiotensin II-induced (AngII-induced) AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalized with macrophages. Trem1 gene deletion (Apoe-/-Trem1-/-), as well as TREM-1 pharmacological blockade with LR-12 peptide, limited both AAA development and severity. Trem1 gene deletion attenuated the inflammatory response in the aorta, with a reduction of Il1b, Tnfa, Mmp2, and Mmp9 mRNA expression, and led to a decreased macrophage content due to a reduction of Ly6Chi classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6Chi monocyte aorta infiltration after AngII infusion through CD62L upregulation and promoted proinflammatory signature in the aorta, resulting in worsening AAA severity. AngII infusion stimulated TREM-1 expression and activation on Ly6Chi monocytes through AngII receptor type I (AT1R). In human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression. Finally, circulating levels of sTREM-1 were increased in patients with AAA when compared with patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in humans.

Published
2021

9. Plasma and genetic determinants of soluble TREM-1 and major adverse cardiovascular events in a prospective cohort of acute myocardial infarction patients. Results from the FAST-MI 2010 study

Author

Salma Kotti, Alain Tedgui, Marie Vandestienne, Marc Derive, Adrien Georges, François Roubille, Sébastien Gibot, Icía Santos-Zas, Nicolas Danchin, Hafid Ait-Oufella, Nabila Bouatia-Naji, Jérémie Joffre, Denis Angoulvant, Tabassome Simon, Mengyao Yu, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Alliance française pour les essais cliniques cardio-vasculaires - French Alliance for Cardiovascular Trials (FACT), French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Faculté de Médecine [Nancy], Université de Lorraine (UL), Service de Réanimation Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), INOTREM SA, Université de Lorraine (UL)-Université de Lorraine (UL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), MORNET, Dominique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)

Subjects
medicine.medical_specialty, TREM-1, Myocardial Infarction, Inflammation, Disease, Acute myocardial infarction, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Myeloid Cells, Prospective Studies, Myocardial infarction, cardiovascular diseases, Non-ST Elevated Myocardial Infarction, Prospective cohort study, Stroke, 030304 developmental biology, Genetic association, 0303 health sciences, business.industry, medicine.disease, Triggering Receptor Expressed on Myeloid Cells-1, Pathophysiology, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Mace
Abstract

International audience; Introduction: Triggering receptor expressing on myeloid cells (TREM)-1 is involved in the pathophysiology of ischemic heart disease. Plasma soluble TREM-1 levels (sTREM-1) has been associated with increased risk of major adverse cardiovascular events (MACE) in acute myocardial infarction (AMI) patients. However, the causative link between TREM-1 and MACE remains unknown and requires further investigation before developing potential therapeutic approaches.Methods and results: Using the serum and DNA data bank from the prospective, nationwide French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction (FAST-MI 2010, N = 1293), we studied the association of plasma levels of sTREM-1 with 9 common genetic variants at the TREM1 locus and their relationship with recurrent MACE over a 3-year follow up. Plasma levels of sTREM-1 were associated with an increased risk of MACEs (death, recurrent MI or stroke) (adjusted HR = 1.86, 95%CI = 1.06–3.26 and HR = 1.11, 95%CI = 0.61–2.02 respectively for tertiles 3 and 2 versus tertile 1, P < 0.001). The study of common variants identified two major genetic determinants of sTREM-1 (rs4714449: beta = −0.11, Padd = 7.85 × 10−5 and rs3804276: beta = 0.18, Padd = 2.65 × 10−11) with a potential role on maintenance and/or differentiation of hematopoietic stem cells. However, associated variants only explained 4% of sTREM-1 variance (P = 2.74 × 10−14). Moreover, the rs4714449 variant, individually and in haplotype, was not significantly associated with MACE (HR = 0.61, 95%CI: 0.35–1.05, P = 0.07).Conclusions: Despite its relationship with increased risk of death, recurrent MI and stroke, genetic determinants of plasma levels of sTREM-1 were not found to be causal prognostic factors in patients with acute myocardial infarction

Published
2021

10. Indoleamine 2 3-dioxygenase knockout limits angiotensin II-induced aneurysm in low density lipoprotein receptor-deficient mice fed with high fat diet

Author

Julien Dairou, Yacine Haddad, Soraya Taleb, Stephane Potteaux, Bruno Esposito, Marie Vandestienne, Sarvenaz Metghalchi, Alain Tedgui, Ziad Mallat, Taleb, Soraya [0000-0002-6650-619X], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, Vascular smooth muscle, T-Lymphocytes, lcsh:Medicine, Apoptosis, 030204 cardiovascular system & hematology, Vascular Medicine, Biochemistry, Monocytes, Muscle, Smooth, Vascular, Fats, White Blood Cells, Mice, chemistry.chemical_compound, Spectrum Analysis Techniques, 0302 clinical medicine, Animal Cells, Medicine and Health Sciences, Indoleamine 2,3-dioxygenase, lcsh:Science, Aorta, Cells, Cultured, Mice, Knockout, Multidisciplinary, TUNEL assay, Cell Death, T Cells, Chemistry, Angiotensin II, Animal Models, Flow Cytometry, Lipids, Experimental Organism Systems, Cell Processes, Spectrophotometry, cardiovascular system, Cytophotometry, Anatomy, Cellular Types, medicine.symptom, Aneurysms, Research Article, medicine.medical_specialty, Cell Survival, Immune Cells, Immunology, Myocytes, Smooth Muscle, Mouse Models, Inflammation, Research and Analysis Methods, Diet, High-Fat, 03 medical and health sciences, Model Organisms, Internal medicine, medicine, Animals, Indoleamine-Pyrrole 2,3,-Dioxygenase, Vascular Diseases, cardiovascular diseases, Blood Cells, Macrophages, lcsh:R, Biology and Life Sciences, Cell Biology, Disease Models, Animal, 030104 developmental biology, Endocrinology, Receptors, LDL, LDL receptor, Cardiovascular Anatomy, Blood Vessels, lcsh:Q, Kynurenine, Aortic Aneurysm, Abdominal
Abstract

Aims Abdominal aortic aneurysm (AAA) is an age-associated disease characterized by chronic inflammation, vascular cell apoptosis and metalloproteinase-mediated extracellular matrix degradation. Despite considerable progress in identifying targets involved in these processes, therapeutic approaches aiming to reduce aneurysm growth and rupture are still scarce. Indoleamine 2–3 dioxygenase 1 (IDO) is the first and rate-limiting enzyme involved in the conversion of tryptophan (Trp) into kynurenine (Kyn) pathway. In this study, we investigated the role of IDO in two different models of AAA in mice. Methods and results Mice with deficiencies in both low density receptor-deficient (Ldlr-/-) and IDO (Ldlr-/-Ido1-/-) were generated by cross-breeding Ido1-/- mice with Ldlr-/-mice. To induce aneurysm, these mice were infused with angiotensin II (Ang II) (1000 ng/min/kg) and fed with high fat diet (HFD) during 28 days. AAAs were present in almost all Ldlr-/- infused with AngII, but only in 50% of Ldlr-/-Ido1-/- mice. Immunohistochemistry at an early time point (day 7) revealed no changes in macrophage and T lymphocyte infiltration within the vessel wall, but showed reduced apoptosis, as assessed by TUNEL assay, and increased α-actin staining within the media of Ldlr-/-Ido1-/- mice, suggesting enhanced survival of vascular smooth muscle cells (VSMCs) in the absence of IDO. In another model of elastase-induced AAA in C57Bl/6 mice, IDO deficiency had no effect on aneurysm formation. Conclusion Our study showed that the knockout of IDO prevented VSMC apoptosis in AngII -treated Ldlr-/- mice fed with HFD, suggesting a detrimental role of IDO in AAA formation and thus would be an important target for the treatment of aneurysm.

Published
2018

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