Src-dependent STAT-3-mediated Expression of Monocyte Chemoattractant Protein-1 Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-induced Vascular Smooth Muscle Cell Migration

Abstract

VSMC3 migration from media to intima plays a determinant role in atherosclerosis and restenosis (1-3). Arachidonic acid (AA) and its oxygenated metabolites, collectively known as eicosanoids, are involved in the maintenance of vascular tone (4, 5). Lipoxygenases (LOXs) are non-heme iron dioxygenases that stereospecifically introduce molecular oxygen into polyunsaturated fatty acids, resulting in the formation of hydroperoxyeicosatetraenoic acids, which are subsequently converted to hydroxyeicosatetraenoic acids (HETEs) (6). Two 15-LOXs, namely, 15-LOX1 and 15-LOX2, have been shown to be expressed in humans (7,8). Both enzymes metabolize linoleic acid to 13(S)-hydroperoxyoctadecadienoic acid and AA to 15(S)-hydroperoxyeicosatetraenoic acid preferentially (9, 10). In regard to their tissue distribution, whereas 15-LOX1 shows a narrow cell-specific expression, including human reticulocytes and airway epithelial cells, 15-LOX2 appears to be expressed in epithelial cell types in cornea, lung, prostate, and skin (11). The studies from our laboratory showed that both 15-LOX1 and 15-LOX2 are expressed in human retinal microvascular endothelial cells (12). Although the presence of 15-LOX2 in VSMC has yet to be reported, these cells express 15-LOX1 (also known as 12/15-LOX in murines) and, when exposed to AA, produce both 15(S)-HETE and 12(S)-HETE (13,14). It is also known that 15-LOX1 and 12/15-LOX are involved in the oxidation of low density lipoprotein, a contributing factor in the pathogenesis of atherosclerosis (15, 16). Furthermore, using either transgenic or knock-out mice models, a number of studies have demonstrated that 15-LOX1 and its murine ortholog 12/15-LOX play a role in atherosclerosis and restenosis (17)(18)(19). In addition, human atheroma homogenates upon incubation with AA converted it mainly to .In recent years LOX products of polyunsaturated fatty acids have also been shown to be potent chemoattractants for resi-* This work was supported, in whole or in part, by National Institutes of Health Grant HL064165 (NHLBI; to G. N. R.

Nuclear Factor of Activated T Cells c1 Mediates p21-activated Kinase 1 Activation in the Modulation of Chemokine-induced Human Aortic Smooth Muscle Cell F-actin Stress Fiber Formation, Migration, and Proliferation and Injury-induced Vascular Wall Remodeling

“…As observed in the case of HASMCs, these findings also infer that NFATc1 acts downstream to Rac1 in mediating cyclin D1 expression, CDK6 and CDK4 activities, and Pak1 activation in the modulation of mouse VSMC migration and proliferation. We have reported previously that injury induces MCP1 expression in a rat carotid artery injury model (12). In agreement with this observation, guide wire injury induced MCP1 expression in the carotid artery, mostly in SMCs, of both WT and SM22Cre:NFATc1 fl/fl mice.…”

“…Formation, Migration, and Proliferation-We have reported previously that vascular injury produces MCP1 and that it mediates VSMC migration and proliferation (12,13). In addition, we have demonstrated that MCP1-induced VSMC migration and proliferation require PKN1 (22), a Rho GTPase effector (30).…”

“…MCP1, also known as CCL2, belongs to the CC chemokine family, and it exhibits profound chemotactic activity toward monocytes, memory T cells, and dendritic cells and, thus, plays a major role in inflammation (9,10). Previously, we and others have shown that MCP1 is produced at the site of vascular injury and is involved in vascular wall remodeling (11)(12)(13). Toward exploring the mechanisms under-* This work was supported, in whole or in part, by NHBLI, National Institutes of lying VSMC migration and proliferation, we have also reported previously that the transcriptional factor nuclear factor of activated T cells c1 (NFATc1) is activated by potent vascular mitogens such as platelet-derived growth factor and thrombin and that inhibition of NFATs blunts their effect on VSMC migration and proliferation and injury-induced neointima formation (14 -16).…”

Vascular Endothelial Tight Junctions and Barrier Function Are Disrupted by 15(S)-Hydroxyeicosatetraenoic Acid Partly via Protein Kinase Cϵ-mediated Zona Occludens-1 Phosphorylation at Threonine 770/772

“…Interestingly, 15-HETE, the major 15-LO product of AA, was also found to be the major metabolite of AA converted by the atherosclerotic arteries (12,13). Similarly, we have reported that overexpression of 15-LO1 or 15-LO2 exacerbates restenosis in response to injury (49,50). In addition, the previous studies by us as well as others have reported the presence of 15-LO or its inhibitor, nordihydroguaiaretic acid-sensitive production of 15(S)-HETE and 13(S)-hydroxyoctadecadienoic acid in response to incubation with AA and linoleic acid, respectively, in both vascular smooth muscle cells and endothelial cells (28,(51)(52)(53)(54).…”

15(S)-hydroxyeicosatetraenoic acid–induced angiogenesis requires Src-mediated Egr-1–dependent rapid induction of FGF-2 expression

“…16,40 Recently, we have shown that forced expression of 15-LOX2 in rat vascular smooth muscle cells or 15-LOX1 in balloon-injured arteries led to production of only 15(S)-HETE. 41,42 Many reports also revealed that angiogenesis plays a critical role in the progression of atherosclerosis and restenosis. 34,35 Our findings showed that 12/15-LOX Ϫ/Ϫ mice fail to exhibit an angiogenic response to AA compared with WT mice.…”