1. Transforming Growth Factor Activity Is a Key Determinant for the Effect of Estradiol on Fatty Streak Deposit in Hypercholesterolemic Mice
- Author
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Barbara Garmy-Susini, Cédric Filipe, Bertrand Calippe, Alexia Schambourg, François Tercé, Pierre Gourdy, Victorine Douin-Echinard, Jean-François Arnal, Francis Bayard, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de diabétologie, Pôle Cardio-Vasculaire et Métabolique, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Departement /u563 : Lipoproteines et Mediateurs Lipidiques, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Diabétologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
- Subjects
MESH: Interleukin-12 ,MESH: Signal Transduction ,MESH: Interleukin-10 ,medicine.medical_treatment ,MESH: Mice, Knockout ,MESH: Drug Implants ,MESH: Antibodies, Monoclonal ,MESH: Atherosclerosis ,Mice ,MESH: Transforming Growth Factor beta1 ,0302 clinical medicine ,MESH: Animals ,MESH: Bone Marrow Transplantation ,Aorta ,Bone Marrow Transplantation ,Drug Implants ,Mice, Knockout ,0303 health sciences ,Estradiol ,Antibodies, Monoclonal ,MESH: Hypercholesterolemia ,Interleukin ,MESH: Aorta ,MESH: Apolipoproteins E ,Interleukin-12 ,Interleukin-10 ,Cytokine ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,MESH: Disease Progression ,MESH: Estradiol ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,MESH: Whole-Body Irradiation ,Whole-Body Irradiation ,Signal Transduction ,medicine.medical_specialty ,MESH: Interferon-gamma ,medicine.drug_class ,Ratón ,Ovariectomy ,Hypercholesterolemia ,MESH: Ovariectomy ,Inflammation ,Biology ,Proinflammatory cytokine ,Transforming Growth Factor beta1 ,Interferon-gamma ,03 medical and health sciences ,Apolipoproteins E ,MESH: Mice, Inbred C57BL ,Internal medicine ,medicine ,Animals ,MESH: Smad3 Protein ,Smad3 Protein ,MESH: Mice ,030304 developmental biology ,Fatty streak ,Atherosclerosis ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,Receptors, LDL ,MESH: Receptors, LDL ,Estrogen ,MESH: Disease Models, Animal ,MESH: Female ,Transforming growth factor - Abstract
Objective— Whereas estradiol prevents fatty streak deposit in immunocompetent apoE −/− or LDLr −/− mice, it is totally ineffective in immunodeficient mice, underlining the key role of immunoinflammation in this effect. In the present work, the role of several major pro- and antiinflammatory cytokines involved in the atheromatous process was evaluated in the effect of estradiol on fatty streak constitution. Methods and Results— The preventive effect of estradiol was fully maintained in LDLr −/− mice grafted with bone marrow from either IFN-γ or interleukin (IL)-12–deficient mice, showing that this beneficial effect was not mediated through a specific decrease in the production of these 2 proinflammatory cytokines. Furthermore, IL-10 −/− apoE −/− mice remained protected by estradiol, excluding a significant contribution of this antiinflammatory cytokine. In contrast, the protective effect of estradiol was (1) associated with enhanced aortic expression of TGF-β1 in apoE −/− mice during early steps of atherogenesis; (2) abolished and even reversed in apoE −/− mice administered with a neutralizing anti–TGF-β antibody; (3) abolished in LDLr −/− mice grafted with bone marrow from Smad3-deficient mice. Conclusions— The status of the TGF-β pathway crucially determines the antiatherogenic effect of estradiol in hypercholesterolemic mice, whereas neither IFN-γ, IL-12, nor IL-10 are specifically involved in this protection.
- Published
- 2007