Oxidized LDL affects smooth muscle cell growth through MAPK-mediated actions on nuclear protein import
ABSTRACT Oxidized low density lipoprotein (oxLDL) plays an important role in the development of atherosclerosis partly through an action on cell proliferation and cell apoptosis. Nuclear protein import (NPI) is critical in regulating gene expression, transcription, and subsequently cell proliferation and apoptosis. The aim of this study was to determine if exposure of vascular smooth muscle cells (VSMC) to oxLDL affects cell growth by inducing alterations in NPI and nuclear pore density. VSMC were exposed for different times to oxLDL. Cells were then injected with a protein import substrate (Alexa488-BSA-NLS) to visually monitor nuclear transport with the confocal microscope. The effect of MAPK inhibitors (SB203580 and PD98059) was investigated and western immunoblottings were also performed. Shorter exposure times of VSMC to oxLDL, but not to native LDL, significantly increased NPI, nuclear pore expression (p62), PCNA expression, and cell number. These changes occurred through an ERK MAPK-dependent mechanism. However, longer exposures to oxLDL decreased NPI, nuclear pore expression, and increased apoptosis marker (cleaved PARP) expression through a p38 MAPK-dependent mechanism. We conclude that limited exposure to oxLDL may influence cell proliferation and apoptosis through an action on nucleocytoplasmic trafficking. The nucleus and NPI may represent a novel therapeutic target to control diseases like atherosclerosis that have changes in cell growth as a central feature.
Article: Effects of dihydropyridine calcium channel blockers on oxidized low-density lipoprotein induced proliferation and oxidative stress of vascular smooth muscle cells.[show abstract] [hide abstract]
ABSTRACT: Dihydropyridine calcium channel blockers (CCBs) are more effective in reducing carotid intima-media thickness (IMT) than other classes of antihypertensive drugs due to their vascular effects. However, the mechanism remains to be elucidated. Ox-LDL induced HUVSMCs proliferation in a time- and dose-dependent manner. When pretreated with three CCBs before 50 μg/ml ox-LDL stimulation, 30 μM lacidipine and 3 μM amlodipine exhibited 27% and 18% decrease of pro-proliferative effect induced by ox-LDL, whereas (S-)-amlodipine did not have any anti-proliferative effect. 30 μM lacidipine inhibited about two-thirds of the ox-LDL induced ROS production in HUVSMCs, whereas amlodipine and (S-)-amlodipine did not have influence on ROS production. The MAPKs pathway inhibitors inhibited the ox-LDL induced proliferation of HUVSMCs. Our study has demonstrated that lipophilic CCBs, such as lacidipine may inhibit ox-LDL induced proliferation and oxidative stress of VSMCs, and that the ROS-MAPKs pathway might be involved in the mechanism.BMC Research Notes 03/2012; 5:168.