Abstract
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 F2alpha, 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.
Highlights
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
Neither SKF525A (100 mM) nor ketoconazole (20 mM) inhibited AA-induced vascular smooth muscle cell (VSMC) motility (Fig. 1C). These results indicate that AA metabolism via the LOX and COX pathways but not the cytochrome P450 (CYP) epoxygenase pathway is required for its effects on VSMC motility
VSMC motility induced by AA alone or by its conversion via the LOX and/ or COX pathways exhibits a requirement for the activation of Jun N-terminal kinase (JNK)
Summary
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. 15(S)-Hydroxyeicosatetraenoic acid and prostaglandin F2a, the 15-LOX and COX metabolites of AA, respectively, that are produced by VSMC at lower doses, were 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.—Dronadula, N., F. Phospholipase A2s play a rate-limiting role in the release of arachidonic acid (AA) from cellular phospholipids [1, 2] Once released, it is reincorporated into membrane phospholipids via esterification involving arachidonoyl-CoA synthase and arachidonoyl-lysophospholipid transferase or converted to eicosanoids by three major enzymatic pathways: cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450 (CYP) epoxygenases [3, 4]. Blaskova contributed to this work. 2 To whom correspondence should be addressed
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