Involvement of cAMP-response element binding protein-1 in arachidonic acid-induced vascular smooth muscle cell motility
Involvement of cAMP-response element binding protein-1 in arachidonic acid-induced vascular smooth muscle cell motility
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DOI：
10.1194/jlr.m500369-jlr200
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发表时间：
2006-04-01
影响因子：
6.5
通讯作者：
Rao, GN
中科院分区：
文献类型：
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作者：
Dronadula, N;Rizvi, F;Rao, GN
花生四烯酸（AA）及其类花生酸代谢产物除了在许多重要的细胞功能中发挥作用外，还参与多种疾病的发病机制，包括动脉粥样硬化和癌症。为了了解这些脂质分子可能影响疾病过程的潜在机制，特别是心血管疾病，我们研究了AA对血管平滑肌细胞（VSMC）运动的影响以及cAMP反应元件结合蛋白-1（CREB-1）在此过程中的作用。AA对VSMC运动产生不同的影响;在较低剂量下，它刺激运动，而在较高剂量下，它是抑制性的。AA诱导的VSMC运动需要通过脂氧合酶（LOX）和环氧合酶（考克斯）途径进行转化。AA刺激细胞外信号调节激酶（ERK），Jun N-末端激酶（JNKs），和p38丝裂原活化蛋白激酶（p38 MAPK）的磷酸化在一个时间依赖性的方式，和这些丝氨酸/苏氨酸激酶的阻断显着衰减AA诱导的VSMC运动。此外，AA刺激CREB-1的磷酸化和活性的方式，也依赖于其代谢转换通过LOX和考克斯途径和激活的ERK和p38 MAPK，但不是JNKs。此外，抑制CREB-1激活抑制AA诱导的VSMC运动。15（S）-羟基二十碳四烯酸和前列腺素F-2 α，AA的15-LOX和考克斯代谢物，分别由VSMC在较低剂量下产生，也被发现刺激这些细胞的运动。总之，这些结果表明，AA诱导VSMC运动的复杂机制，涉及其代谢通过LOX和考克斯途径，以及ERK和p38 MAPK依赖性和JNK非依赖性激活CREB-1。
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 F-2 alpha, 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.