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Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163
Published, JLR Papers in Press, December 28, 2006.
1 F. Rizvi and E. Blaskova contributed equally to this work.
2 To whom correspondence should be addressed. e-mail: grao{at}physio1.utmem.edu
In addition to their role in many vital cellular functions, arachidonic acid (AA) and its eicosanoid metabolites are involved in the pathogenesis of several diseases, including atherosclerosis and cancer. To understand the potential mechanisms by which these lipid molecules could influence the disease processes, particularly cardiovascular diseases, we studied AA's effects on vascular smooth muscle cell (VSMC) motility and the role of cAMP-response element binding protein-1 (CREB-1) in this process. AA exerted differential effects on VSMC motility; at lower doses, it stimulated motility, whereas at higher doses, it was inhibitory. AA-induced VSMC motility requires its conversion via the lipoxygenase (LOX) and cyclooxygenase (COX) pathways. AA stimulated the phosphorylation of extracellular signal-regulated kinases (ERKs), Jun N-terminal kinases (JNKs), and p38 mitogen-activated protein kinase (p38MAPK) in a time-dependent manner, and blockade of these serine/threonine kinases significantly attenuated AA-induced VSMC motility. In addition, AA stimulated CREB-1 phosphorylation and activity in a manner that was also dependent on its metabolic conversion via the LOX and COX pathways and the activation of ERKs and p38MAPK but not JNKs. Furthermore, suppression of CREB-1 activation inhibited AA-induced VSMC motility. 15(S)-Hydroxyeicosatetraenoic acid and prostaglandin F2
, the 15-LOX and COX metabolites of AA, respectively, that are produced by VSMC at lower doses, were also found to stimulate motility in these cells. Together, these results suggest that AA induces VSMC motility by complex mechanisms involving its metabolism via the LOX and COX pathways as well as the ERK- and p38MAPK-dependent and JNK-independent activation of CREB-1.
Supplementary key words cell migration • adenosine 3',5'-cyclic monophosphate • cyclooxygenase • fatty acid • lipoxygenase • mitogen-activated protein kinases
Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; CREB-1, cAMP-response element binding protein-1; CYP, cytochrome P450; ERK, extracellular signal-regulated kinase; ETI, 5,8,11-eicosatriynoic acid; HETE, hydroxyeicosatetraenoic acid; JNK, Jun N-terminal kinase; LOX, lipoxygenase; PGF2, prostaglandin F2; p38MAPK, p38 mitogen-activated protein kinase; VSMC, vascular smooth muscle cell
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