oxLDL induces endothelial cell proliferation via Rho/ROCK/Akt/p27kip1 signaling: opposite effects of oxLDL and cholesterol loading

Am J Physiol Cell Physiol. 2017 Sep 1;313(3):C340-C351. doi: 10.1152/ajpcell.00249.2016. Epub 2017 Jul 12.


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 (Cu2+-oxLDL) and lipoxygenase-oxidized LDL (LPO-oxLDL), on proliferation of human aortic endothelial cells (HAECs). Cu2+-oxLDL enhanced HAECs' proliferation in a dose- and degree of oxidation-dependent manner. Similarly, LPO-oxLDL also enhanced HAEC proliferation. Mechanistically, both Cu2+-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 (p27kip1). Both Cu2+-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 Cu2+- 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 p27kip1 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.

Keywords: Rho kinase; oxidized modifications of low-density lipoproteins.

MeSH terms

  • Cell Proliferation / physiology
  • Cells, Cultured
  • Cholesterol / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism*
  • Endothelial Cells / cytology
  • Endothelial Cells / physiology*
  • Gene Expression Regulation, Enzymologic / physiology
  • Humans
  • Lipoproteins, LDL / metabolism*
  • Oncogene Protein v-akt / metabolism*
  • Signal Transduction / physiology
  • rho-Associated Kinases / metabolism*


  • Lipoproteins, LDL
  • oxidized low density lipoprotein
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cholesterol
  • Oncogene Protein v-akt
  • rho-Associated Kinases