Src-dependent STAT-3-mediated expression of monocyte chemoattractant protein-1 is required for 15(S)-hydroxyeicosatetraenoic acid-induced vascular smooth muscle cell migration.
To understand the role of human 15-lipoxygenase 1 (15-LOX1) in vascular wall remodeling, we have studied the effect of the major 15-LOX1 metabolite of arachidonic acid, 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), on vascular smooth muscle cell (VSMC) migration both in vitro and in vivo. Among 5(S)-HETE, 12(S)-HETE, and 15(S)-HETE, 15(S)-HETE potentially stimulated more vascular smooth muscle cell (VSMC) migration. In addition, 15(S)-HETE-induced VSMC migration was dependent on Src-mediated activation of signal transducer and activator of transcription-3 (STAT-3). 15(S)-HETE also induced monocyte chemoattractant protein-1 (MCP-1) expression via Src-STAT-3 signaling, and neutralizing anti-MCP-1 antibodies completely negated 15(S)-HETE-induced VSMC migration. Cloning and characterization of a 2.6-kb MCP-1 promoter revealed the presence of four putative STAT-binding sites, and the site that is proximal to the transcription start site was found to be essential for 15(S)-HETE-induced Src-STAT-3-mediated MCP-1 expression. Rat carotid arteries that were subjected to balloon injury and transduced with Ad-15-LOX1 upon exposure to [(3)H]arachidonic acid ex vivo produced 15-HETE as a major eicosanoid and enhanced balloon injury-induced expression of MCP-1 in smooth muscle cells in Src and STAT-3-dependent manner in vivo. Adenovirus-mediated delivery of 15-LOX1 into rat carotid artery also led to recruitment and homing of macrophages to medial region in response to injury. In addition, transduction of Ad-15-LOX1 into arteries enhanced balloon injury-induced smooth muscle cell migration from media to intima and neointima formation. These results show for the first time that 15-LOX1-15(S)-HETE axis plays a major role in vascular wall remodeling after balloon angioplasty.
Potula
Harihara S K
HS
Department of Physiology, The University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Wang
Dong
D
Quyen
Dong Van
DV
Singh
Nikhlesh K
NK
Kundumani-Sridharan
Venkatesh
V
Karpurapu
Manjula
M
Park
Edwards A
EA
Glasgow
Wayne C
WC
Rao
Gadiparthi N
GN
D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D066298:In Vitro Techniques; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D018932:Chemokine CCL2; D006893:Hydroxyeicosatetraenoic Acids; D050796:STAT3 Transcription Factor; D001093:Arachidonate 15-Lipoxygenase; D016392:Proto-Oncogene Proteins pp60(c-src)