Kothapalli Devashish, Fuki Ilia, Ali Kamilah, Stewart Sheryl A, Zhao Liang, Yahil Ron, Kwiatkowski David, Hawthorne Elizabeth A, FitzGerald Garret A, Phillips Michael C, Lund-Katz Sissel, Puré Ellen, Rader Daniel J, Assoian Richard K
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6084, USA.
J Clin Invest. 2004 Feb;113(4):609-18. doi: 10.1172/JCI19097.
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.
高密度脂蛋白（HDL）及其相关载脂蛋白APOE可抑制小鼠主动脉平滑肌细胞进入S期。我们在此报告，APOE的抗有丝分裂作用定位于N端受体结合域，APOE及其N端结构域可抑制细胞周期蛋白A启动子的激活，且这些作用涉及依赖口袋蛋白和不依赖口袋蛋白的两条途径。这些抗有丝分裂作用与前列环素受体IP激活后的作用极为相似。实际上，我们发现HDL和APOE通过刺激Cox-2表达来抑制主动脉平滑肌细胞周期进程，从而导致前列环素合成，并对细胞周期蛋白A基因产生IP依赖的抑制作用。在人主动脉平滑肌细胞以及使用过表达APOE的小鼠进行的体内实验中也检测到了类似结果。我们的研究结果确定Cox-2基因为APOE信号传导的一个靶点，将HDL和APOE与IP的作用联系起来，并描述了HDL和APOE心脏保护作用的一个潜在新机制。
