oxLDL induces endothelial cell proliferation via Rho/ROCK/Akt/p27 kip1 signaling: opposite effects of oxLDL and cholesterol loading.

Autor:	Zhang C; Division of Pulmonary and Critical Care, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and., Adamos C; Division of Pulmonary and Critical Care, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and., Oh MJ; Division of Pulmonary and Critical Care, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and., Baruah J; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois., Ayee MAA; Division of Pulmonary and Critical Care, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and., Mehta D; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois., Wary KK; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois., Levitan I; Division of Pulmonary and Critical Care, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and levitan@uic.edu.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Cell physiology [Am J Physiol Cell Physiol] 2017 Sep 01; Vol. 313 (3), pp. C340-C351. Date of Electronic Publication: 2017 Jul 12.
DOI:	10.1152/ajpcell.00249.2016
Abstrakt:	Oxidized modifications of LDL (oxLDL) play a key role in the development of endothelial dysfunction and atherosclerosis. However, the underlying mechanisms of oxLDL-mediated cellular behavior are not completely understood. Here, we compared the effects of two major types of oxLDL, copper-oxidized LDL (Cu 2+ -oxLDL) and lipoxygenase-oxidized LDL (LPO-oxLDL), on proliferation of human aortic endothelial cells (HAECs). Cu 2+ -oxLDL enhanced HAECs' proliferation in a dose- and degree of oxidation-dependent manner. Similarly, LPO-oxLDL also enhanced HAEC proliferation. Mechanistically, both Cu 2+ -oxLDL and LPO-oxLDL enhance HAEC proliferation via activation of Rho, Akt phosphorylation, and a decrease in the expression of cyclin-dependent kinase inhibitor 1B (p27 kip1 ). Both Cu 2+ -oxLDL or LPO-oxLDL significantly increased Akt phosphorylation, whereas an Akt inhibitor, MK2206, blocked oxLDL-induced increase in HAEC proliferation. Blocking Rho with C3 or its downstream target ROCK with Y27632 significantly inhibited oxLDL-induced Akt phosphorylation and proliferation mediated by both Cu 2+ - and LPO-oxLDL. Activation of RhoA was blocked by Rho-GDI-1, which also abrogated oxLDL-induced Akt phosphorylation and HAEC proliferation. In contrast, blocking Rac1 in these cells had no effect on oxLDL-induced Akt phosphorylation or cell proliferation. Moreover, oxLDL-induced Rho/Akt signaling downregulated cell cycle inhibitor p27 kip1 Preloading these cells with cholesterol, however, prevented oxLDL-induced Akt phosphorylation and HAEC proliferation. These findings provide a new understanding of the effects of oxLDL on endothelial proliferation, which is essential for developing new treatments against neovascularization and progression of atherosclerosis. (Copyright © 2017 the American Physiological Society.)
Databáze:	MEDLINE
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