© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells
aDepartment of Internal Medicine, University of Arkansas for Medical Sciences, Mail Slot 532, 4301 W Markham, Little Rock, AR 72205, USA
bDepartment of Physiology and Biophysics, University of Arkansas for Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
* Corresponding author. Tel.: +1-501-296-1401; fax: +1-501-686-6180. mehtajl{at}uams.edu
Background and objectives: Our previous studies have shown that oxidized low-density lipoprotein (ox-LDL) and angiotensin II (Ang II) influence each other's action in endothelial cells. This study was designed to examine the regulation by ox-LDL of the expression of angiotensin converting enzyme (ACE) gene in human coronary artery endothelial cells (HCAECs). In addition, we studied the effect of the HMG CoA reductase inhibitor simvastatin on this interaction. Methods and results: Cultured HCAECs were incubated with ox-LDL (10–80 µg/ml) for 1–24 h. Ox-LDL increased the expression of ACE in a concentration- and time-dependent fashion. The upregulation of ACE expression in response to ox-LDL was mediated by its endothelial receptor LOX-1, since pretreatment of HCAECs with a blocking antibody to LOX-1 prevented the expression of ACE (P<0.01). Native-LDL had no significant effect on ACE expression. In this process, ox-LDL-induced activation of mitogen-activated protein kinase (MAPK p42/44) played an important role, since pretreatment of HCAECs with the MAPK p42/44 inhibitor (PD98059, 10 µM) inhibited MAPK activation and subsequently attenuated the expression of ACE (P<0.01 vs. ox-LDL alone). In other experiments, we pretreated HCAECs with simvastatin (10 µM) and then exposed the cells to ox-LDL. Simvastatin markedly attenuated ox-LDL-induced MAPK activation, and concurrently reduced ACE expression (P<0.01 vs. ox-LDL alone). Conclusions: Our observations provide direct evidence that ox-LDL via LOX-1 activation induces ACE gene expression in HCAECs, and MAPK activation plays a signal transduction role in this process. Simvastatin, which inhibits MAPK activation, also blocks ox-LDL-mediated upregulation of ACE.
KEYWORDS ACE inhibitors; Angiotensin; Endothelial function; Gene expression; Lipoproteins
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