on August 9, 2007
Published online before print August 9, 2007, doi: 10.1161/ATVBAHA.107.150300
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Submitted on January 15, 2007
Accepted on July 6, 2007
Transforming Growth Factor Activity Is a Key Determinant for the Effect of Estradiol on Fatty Streak Deposit in Hypercholesterolemic Mice
Pierre Gourdy *;
From the Institut National de la Santé et de la Recherche Médicale, INSERM U858 (P.G., A.S., C.F., V.D.E., B.G.S., B.C., F.B., J.F.A.), Institut de Médecine Moléculaire de Rangueil, Toulouse, France; Service de Diabétologie (P.G.), Pôle Cardio-Vasculaire et Métabolique, CHU Toulouse Rangueil, France; and INSERM U563 (F.T.), Département Lipoprotéines et Médiateurs Lipidiques, CHU Toulouse Purpan, France.
* To whom correspondence should be addressed. E-mail: gourdyp{at}toulouse.inserm.fr.
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-
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-
1 in apoE-/- mice during early steps of atherogenesis; (2) abolished and even reversed in apoE-/- mice administered with a neutralizing anti–TGF- antibody; (3) abolished in LDLr-/- mice grafted with bone marrow from Smad3-deficient mice.
Conclusions—The status of the TGF- pathway crucially determines the antiatherogenic effect of estradiol in hypercholesterolemic mice, whereas neither IFN-, IL-12, nor IL-10 are specifically involved in this protection.
Key words: atherosclerosis • inflammation • cytokine • TGF-
•
estrogen
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