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 micro g/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 micro g/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-beta isoform played a critical role in the expression of MMPs, because the PKC-beta inhibitor hispidin reduced ox-LDL-induced activation of PKC and the expression of MMPs. Other PKC subunits (alpha, gamma, and epsilon) 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-beta subunit plays an important signaling role.
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 micro g/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 micro g/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-beta isoform played a critical role in the expression of MMPs, because the PKC-beta inhibitor hispidin reduced ox-LDL-induced activation of PKC and the expression of MMPs. Other PKC subunits (alpha, gamma, and epsilon) 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-beta subunit plays an important signaling role.
Authors: Dayuan Li; Amit R Patel; Alexander L Klibanov; Christopher M Kramer; Mirta Ruiz; Bum-Yong Kang; Jawahar L Mehta; George A Beller; David K Glover; Craig H Meyer Journal: Circ Cardiovasc Imaging Date: 2010-05-04 Impact factor: 7.792
Authors: Amie K Lund; JoAnn Lucero; Melissa Harman; Michael C Madden; Jacob D McDonald; Jean Clare Seagrave; Matthew J Campen Journal: Am J Respir Crit Care Med Date: 2011-04-14 Impact factor: 21.405
Authors: J Thomas Grayston; Robert J Belland; Gerald I Byrne; Cho Chou Kuo; Julius Schachter; Walter E Stamm; Guangming Zhong Journal: Pathog Dis Date: 2014-12-04 Impact factor: 3.166