Antiapoptotic and Proliferative Effects of Low Concentrations of 7 beta-Hydroxycholesterol in Human Endothelial Cells via ERK Activation

作者：Trevisi Lucia^*; Bertoldo Alessandro; Agnoletto Laura; Poggiani Chiara; Cusinato Federico; Luciani Sisto

来源：Journal of Vascular Research, 2010, 47(3): 241-251.

DOI：10.1159/000255967

• 7 beta-Hydroxycholesterol
• Endothelial apoptosis
• Endothelial cell proliferation
• ERK
• Reactive oxygen species

The atherogenic potential of oxidized low-density lipoproteins (oxLDL) has been correlated to their 7 beta-hydroxycholesterol (7 beta OHC) content; oxLDLs have a dual effect on endothelial cell viability, inducing apoptosis or proliferation depending on the concentration. Considering that 7 beta OHC is apoptotic for endothelial cells at concentrations >= 20 mu g/ml, a study on the effect of lower concentrations of 7 beta OHC on human umbilical vein endothelial cells (HUVECs) was undertaken. 7 beta OHC (1-10 mu g/ml) increased 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction of growth-factor-deprived HUVECs. This effect was due to the increased cell proliferation, determined by [ 3 H] thymidine incorporation, and the reduction of apoptosis, revealed by the decreased caspase-3 activation and annexin V staining. 7 beta OHC also protected against staurosporine apoptosis. 7 beta OHC induced an increase in intracellular ROS antagonized by N-acetylcysteine; however, HUVECs treatment with the antioxidant did not inhibit the effects of 7 beta OHC. 7 beta OHC produced an increase in extracellular signal-regulated kinase (ERK) phosphorylation that was blocked by inhibitors of store-operated calcium entry 2-aminoethoxydiphenyl borate and gadolinium. MEK inhibition with PD98059 or U0126 as well as store-operated calcium entry inhibition antagonized the effect of 7 beta OHC. The results suggest that 7 beta OHC promotes HUVECs survival and proliferation by a mechanism independent of ROS production and involving calcium-dependent activation of ERK.

• 出版日期2010