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(Circulation. 2003;107:612.)
© 2003 American Heart Association, Inc.

Basic Science Reports

LOX-1 Mediates Oxidized Low-Density Lipoprotein-Induced Expression of Matrix Metalloproteinases in Human Coronary Artery Endothelial Cells

Dayuan Li, MD, PhD; Ling Liu, MD; Hongjiang Chen, MD; Tatsuya Sawamura, MD, PhD; Subramanian Ranganathan, PhD; Jawahar L. Mehta, MD, PhD

From the Departments of Medicine and Physiology and Biophysics, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock (D.L., L.L., S.R., J.L.M.), and Department of Bioscience, National Cardiovascular Center Research Institute, Osaka, Japan (T.S.).

Correspondence to J.L. Mehta, MD, PhD, Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 532, Little Rock, AR 72205. E-mail mehtajl{at}uams.edu

Background— Oxidized LDL (ox-LDL) accumulation in the atherosclerotic region may enhance plaque instability. Both accumulation of ox-LDL and expression of its lectin-like receptor, LOX-1, have been shown in atherosclerotic regions. This study was designed to examine the role of LOX-1 in the modulation of metalloproteinases (MMP-1 and MMP-3) in human coronary artery endothelial cells (HCAECs).

Methods and Results— HCAECs were incubated with ox-LDL (10 to 80 µg/mL) for 1 to 24 hours. Ox-LDL increased the expression of MMP-1 (collagenase) and MMP-3 (stromelysin-1) in a concentration- and time-dependent manner. Ox-LDL also increased collagenase activity. Ox-LDL did not significantly affect the expression of tissue inhibitors of metalloproteinases. Native LDL had no effect on the expression of MMPs. The effects of ox-LDL were mediated by its endothelial receptor, LOX-1, because pretreatment of HCAECs with a blocking antibody to LOX-1 (JTX92, 10 µg/mL) prevented the expression of MMPs in response to ox-LDL (P<0.01). In parallel experiments, ox-LDL caused the activation of protein kinase C (PKC), which was inhibited by LOX-1 antibody. The PKC-ß isoform played a critical role in the expression of MMPs, because the PKC-ß inhibitor hispidin reduced ox-LDL-induced activation of PKC and the expression of MMPs. Other PKC subunits (, , and ) did not affect the expression of MMPs.

Conclusions— These findings indicate that ox-LDL, via LOX-1 activation, modulates the expression and activity of MMPs in HCAECs. In this process, activation of the PKC-ß subunit plays an important signaling role.

Key Words: endothelium • metalloproteinases • receptors, oxidized LDL • lipoproteins • kinases

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