Estrogen attenuates vascular remodeling in Lp(a) transgenic mice.
OBJECTIVE
Although it is well known that Lipoprotein(a) (Lp(a)) is an atherogenic lipoprotein and an independent risk factor for cardiovascular disease, there is no confirmed therapy to decrease Lp(a) or prevent atherosclerosis induced by Lp(a). Thus, it is mandatory to develop novel therapy to prevent atherosclerosis in high Lp(a) concentration. Here, we focused on the effect of estrogen on Lp(a) level and Lp(a)-induced vascular remodeling.


METHODS
We employed Lp(a) transgenic mice (human apo(a) yeast artificial chromosome (YAC) and human apoB double transgenic mice). Vascular remodeling was induced by ligation of the common carotid artery and the effect of estrogen was evaluated in female mice after ovariectomy with or without estrogen replacement.


RESULTS
Estrogen deficiency caused by ovariectomy increased serum Lp(a), and continuous replacement of 17beta-estradiol (20 microg/kg/day) reversed the change. In the vascular remodeling model induced by carotid artery occlusion, neointima formation was significantly increased in ovariectomized female Lp(a) transgenic mice, but few in male Lp(a) transgenic mice, as compared to wild FVB mice. Importantly, continuous replacement of estrogen in ovariectomized mice significantly attenuated it. In cultured endothelial cells and macrophages, addition of Lp(a) increased mRNA of ICAM-1, VCAM-1, E-selectin and MCP-1 in endothelial cells and TNF-alpha, IL-1beta and MCP-1 in macrophages in a dose-dependent manner. Importantly, pre-treatment with estrogen attenuated these changes in a dose-dependent manner.


CONCLUSIONS
Estrogen negatively regulates both plasma Lp(a) level and Lp(a)-induced vascular remodeling, suggesting that estrogen might be a strong candidate to reduce serum Lp(a) concentration.
Nakagami
Futoshi
F
Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Japan.
Nakagami
Hironori
H
Osako
Mariana Kiomy
MK
Iwabayashi
Masaaki
M
Taniyama
Yoshiaki
Y
Doi
Takefumi
T
Shimizu
Hideo
H
Shimamura
Munehisa
M
Rakugi
Hiromi
H
Morishita
Ryuichi
R
D000818:Animals; D002339:Carotid Arteries / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects; D004958:Estradiol / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008026:Ligation; D017270:Lipoprotein(a) / Q000097:blood / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010052:Ovariectomy; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017539:Tunica Intima / Q000254:growth & development; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D019040:E-Selectin; D053583:Interleukin-1beta; D017270:Lipoprotein(a); D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D004958:Estradiol