Transforming growth factor activity is a key determinant for the effect of estradiol on fatty streak deposit in hypercholesterolemic mice. - Archive ouverte HAL Access content directly
Journal Articles Arteriosclerosis, Thrombosis, and Vascular Biology Year : 2007

Transforming growth factor activity is a key determinant for the effect of estradiol on fatty streak deposit in hypercholesterolemic mice.

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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-gamma 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-beta1 in apoE-/- mice during early steps of atherogenesis; (2) abolished and even reversed in apoE-/- mice administered with a neutralizing anti-TGF-beta antibody; (3) abolished in LDLr-/- mice grafted with bone marrow from Smad3-deficient mice. CONCLUSIONS: The status of the TGF-beta pathway crucially determines the antiatherogenic effect of estradiol in hypercholesterolemic mice, whereas neither IFN-gamma, IL-12, nor IL-10 are specifically involved in this protection.

Dates and versions

inserm-00409639 , version 1 (11-08-2009)

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Pierre Gourdy, Alexia Schambourg, Cédric Filipe, Victorine Douin-Echinard, Barbara Garmy-Susini, et al.. Transforming growth factor activity is a key determinant for the effect of estradiol on fatty streak deposit in hypercholesterolemic mice.. Arteriosclerosis, Thrombosis, and Vascular Biology, 2007, 27 (10), pp.2214-21. ⟨10.1161/ATVBAHA.107.150300⟩. ⟨inserm-00409639⟩
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