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


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.
Gourdy
Pierre
P
INSERM U858, Institut de Médecine Moléculaire de Rangueil, BP 84225, 31432 Toulouse Cedex 4, France. gourdyp@toulouse.inserm.fr
Schambourg
Alexia
A
Filipe
Cédric
C
Douin-Echinard
Victorine
V
Garmy-Susini
Barbara
B
Calippe
Bertrand
B
Tercé
François
F
Bayard
Francis
F
Arnal
Jean-François
JF
D000818:Animals; D000911:Antibodies, Monoclonal; D001011:Aorta / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D018450:Disease Progression; D004343:Drug Implants; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D006937:Hypercholesterolemia / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010052:Ovariectomy; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism*; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D004343:Drug Implants; D011973:Receptors, LDL; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D018664:Interleukin-12; D004958:Estradiol; D007371:Interferon-gamma