Antimitogenic effects of HDL and APOE mediated by Cox-2–dependent IP activation
Devashish Kothapalli, … , Daniel J. Rader, Richard K. Assoian
Devashish Kothapalli, … , Daniel J. Rader, Richard K. Assoian
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):609-618. https://doi.org/10.1172/JCI19097.
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Article Cardiology

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

Abstract

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.

Authors

Devashish Kothapalli, Ilia Fuki, Kamilah Ali, Sheryl A. Stewart, Liang Zhao, Ron Yahil, David Kwiatkowski, Elizabeth A. Hawthorne, Garret A. FitzGerald, Michael C. Phillips, Sissel Lund-Katz, Ellen Puré, Daniel J. Rader, Richard K. Assoian

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Figure 1

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HDL and APOE inhibit S-phase entry in aortic SMCs. (a) Quiescent aortic ...
HDL and APOE inhibit S-phase entry in aortic SMCs. (a) Quiescent aortic SMCs were trypsinized and replated with 10% FBS for selected times in the absence (control) or presence of 50 μg/ml LDL, HDL, or APOE-depleted HDL. (b) Quiescent cells were stimulated with 10% FBS for 48 hours in the presence of increasing concentrations of LDL, HDL, or APOE-deficient HDL. (c) Quiescent aortic SMCs were trypsinized, added to 35-mm dishes containing coverslips, and stimulated with 10% FBS for 48 hours in the presence of increasing concentrations of APOA-I, APOE, APOE22, or APOE10. BrdU incorporation into nuclei was determined by immunofluorescence microscopy. Results show the mean ± SEM, n = 3, *P < 0.01 as compared with cells treated with 10% FBS alone.