Participation of 5-lipoxygenase-derived LTB(4) in 4-hydroxynonenal-enhanced MMP-2 production in vascular smooth muscle cells.
5-Lipoxygenase (5-LO) has been suggested as a modulator of atherosclerotic plaque instability, however, its role in MMP production in vascular smooth muscle cells (VSMC) is still unclear. Thus, this study investigated the role of 5-LO in HNE-enhanced MMP-2 production in VSMC, and the mechanisms by which this enzyme could be activated by HNE. VSMC stimulated with HNE (1 microM) produced MMP-2, which was markedly attenuated in 5-LO-deficient VSMC as well as in cells pretreated with a FLAP inhibitor, MK886, confirming a role for 5-LO metabolites in HNE-enhanced MMP-2 production. Related to these results, HNE increased nuclear translocation of 5-LO promoting 5-LO activity, which was attenuated not only by SB203580, a p38 MAPK inhibitor, but also by PD98059, an ERK inhibitor. In parallel, phosphorylation of p38 MAPK and ERK occurred as early as 15 min after exposure to HNE, suggesting a potential role for p38 MAPK and ERK pathways in HNE-induced activation of 5-LO. Among leukotriene (LT) receptor antagonists, U-75302, a BLT receptor antagonist, but not MK-571 and Rev-5901, cysLT receptor antagonists, showed an inhibitory effect on HNE-enhanced MMP-2 production. Moreover, MMP-2 production in VSMC was also significantly increased by LTB(4), but not by LTC(4) and LTD(4). Collectively, these data suggest that 5-LO mediates HNE-enhanced MMP-2 production via LTB(4)-BLT receptor pathways, consequently leading to atherosclerotic plaque instability.
Seo
Kyo W
KW
MRC for Ischemic Tissue Regeneration and Medical Research Institute, Pusan National University, Yangsan, Gyeongnam, Republic of Korea.
Lee
Seung J
SJ
Kim
Chae E
CE
Yun
Mi R
MR
Park
Hye M
HM
Yun
Jung W
JW
Bae
Sun S
SS
Kim
Chi D
CD
D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D007975:Leukotriene B4 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000187:drug effects*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*
D000447:Aldehydes; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C027576:4-hydroxy-2-nonenal