Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells

doi:10.1016/S0008-6363(02)00674-0

Cardiovascular Research 2003 57(1):238-243; doi:10.1016/S0008-6363(02)00674-0
© 2003 by European Society of Cardiology

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Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells

Dayuan Li^a^,b, Robin M. Singh^a^,b, Ling Liu^a^,b, Hongjiang Chen^a^,b, Balkrishna M. Singh^a^,b, Nelly Kazzaz^a^,b and Jawahar L. Mehta^a^,b^,*

^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 thatoxidized 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-LDLof the expression of angiotensin converting enzyme (ACE) genein human coronary artery endothelial cells (HCAECs). In addition,we studied the effect of the HMG CoA reductase inhibitor simvastatinon this interaction. Methods and results: Cultured HCAECs wereincubated with ox-LDL (10–80 µg/ml) for 1–24h. Ox-LDL increased the expression of ACE in a concentration-and time-dependent fashion. The upregulation of ACE expressionin response to ox-LDL was mediated by its endothelial receptorLOX-1, since pretreatment of HCAECs with a blocking antibodyto LOX-1 prevented the expression of ACE (P<0.01). Native-LDLhad 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 ofHCAECs with the MAPK p42/44 inhibitor (PD98059, 10 µM)inhibited MAPK activation and subsequently attenuated the expressionof ACE (P<0.01 vs. ox-LDL alone). In other experiments, wepretreated HCAECs with simvastatin (10 µM) and then exposedthe cells to ox-LDL. Simvastatin markedly attenuated ox-LDL-inducedMAPK activation, and concurrently reduced ACE expression (P<0.01vs. ox-LDL alone). Conclusions: Our observations provide directevidence that ox-LDL via LOX-1 activation induces ACE gene expressionin HCAECs, and MAPK activation plays a signal transduction rolein 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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