Role of inflammatory cytokines in the effect of estradiol on atheroma.
1. Although hormonal therapy (HT) may increase the risk of coronary heart disease (CHD) and stroke in postmenopausal women, epidemiological studies (protection in premenopausal women) suggest and experimental studies (prevention of fatty streak development in animals) demonstrate a major atheroprotective action of estradiol (E2). The understanding of the deleterious and beneficial effects of oestrogens is thus required. 2. The immuno-inflammatory system plays a key role in the development of fatty streak deposit as well as in the rupture of the atherosclerotic plaque. Although E2 favours an anti-inflammatory effect in vitro (cultured cells), it rather elicits a pro-inflammatory response in vivo involving several subpopulations of the immuno-inflammatory system, which could contribute to plaque destabilization. The functional role of several cytokines was explored in hypercholesterolemic mice. The atheroprotective effect of E2 was fully maintained in mice deficient in interferon-g or interleukin-12, as well as IL-10. In contrast, the protective effect of estradiol was abolished and even reversed in hypercholesterolemic mice given a neutralizing anti-transforming growth factor-b (TGF-b) antibody. Endothelium is another important target for E2, since it not only potentiates endothelial nitric oxide and prostacyclin production, but also controls trafficking of the populations of the immuno-inflammatory system. 3. To conclude, the respective actions of oestrogens on the cell populations involved in the pathophysiology of atherothrombosis may be influenced, among others, by the timing of HT initiation, the status of the vessel wall and, as recently demonstrated the status of the TGF-b pathway.
Gourdy
P
P
Department of Vascular Biology and Atherothrombosis, INSERM U858-I2MR, CHU Toulouse-Rangueil, Toulouse, France.
Calippe
B
B
Laurell
H
H
Trémollières
F
F
Douin-Echinard
V
V
Lenfant
F
F
Bayard
F
F
Guery
J C
JC
Arnal
J F
JF
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D006937:Hypercholesterolemia; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016212:Transforming Growth Factor beta
D016207:Cytokines; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D004958:Estradiol; D007371:Interferon-gamma