Antimitogenic effects of HDL and APOE mediated by cox-2-dependent IP activation

被引:40
作者
Kothapalli, D
Fuki, I
Ali, K
Stewart, SA
Zhao, L
Yahil, R
Kwiatkowski, D
Hawthorne, EA
FitzGerald, GA
Phillips, MC
Lund-Katz, S
Puré, E
Rader, D
Assoian, RK
机构
[1] Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA
[3] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA
[4] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Abramson Res Ctr, Philadelphia, PA 19104 USA
[5] Ludwig Inst Canc Res, New York, NY USA
关键词
D O I
10.1172/JCI200419097
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
HDL and its associated apo, APOE, inhibit S-phase entry of murine aortic smooth muscle cells. We report here that the antimitogenic effect of APOE maps to the N-terminal receptor-binding domain, that APOE and its N-terminal domain inhibit activation of the cyclin A promoter, and that these effects involve both pocket protein-dependent and independent pathways. These antimitogenic effects closely resemble those seen in response to activation of the prostacyclin receptor IP. indeed, we found that HDL and APOE suppress aortic smooth muscle cell cycle progression by stimulating Cox-2 expression, leading to prostacyclin synthesis and an IP-dependent inhibition of the cyclin A gene. Similar results were detected in human aortic smooth muscle cells and in vivo using mice overexpressing APOE. Our results identify the Cox-2 gene as a target of APOE signaling, link HDL and APOE to IP action, and describe a potential new basis for the cardioprotective effect of HDL and APOE.
引用
收藏
页码:609 / 618
页数:10
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