Phosphatidylinositide 3-kinase regulates angiotensin II-induced cytosolic phospholipase A2 activity and growth in vascular smooth muscle cells.
Phosphatidylinositide 3-kinase regulates angiotensin II-induced cytosolic phospholipase A2 activity and growth in vascular smooth muscle cells.
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磷脂酰肌醇 3-激酶调节血管紧张素 II 诱导的胞质磷脂酶 A2 活性和血管平滑肌细胞的生长。
DOI：
10.1016/s0003-9861(02)00066-8
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发表时间：
2002
影响因子：
3.9
通讯作者：
E. J. Freeman
中科院分区：
文献类型：
--
作者：
Tonous N. Silfani;E. J. Freeman
血管紧张素（Ang） II通过at1受体作为血管平滑肌细胞（VSMC）的丝裂原，通过刺激多种信号机制，包括酪氨酸激酶和丝裂原活化蛋白激酶（MAPK）。此外，胞质磷脂酶A2（cPLA2）依赖于花生四烯酸（AA）的释放与VSMC生长有关，我们已经报道过Ang II通过at1受体刺激cPLA2活性。Ang II与cpla2激活的耦合似乎涉及MAPK的上游和下游机制，例如AA刺激MAPK活性，使cpla2磷酸化，进一步增强AA的释放。然而，负责激活cpla2的上游机制尚未明确定义。一种可能包括磷脂酰肌苷3-激酶（PI3K），因为PI3K已被报道参与与MAPK激活相关的上游信号事件。然而，目前尚不清楚PI3K是否参与了Ang ii诱导的cpla2激活，或者该机制是否与Ang ii介导的VSMC生长有关。因此，我们利用培养的大鼠VSMC来检测PI3K在Ang II依赖性cPLA2磷酸化、AA释放和Ang II诱导的生长中的作用。VSMC暴露于Ang II （100 nM）下增加了[3H]胸苷的掺入、细胞数量和[3H]AA的释放。此外，通过Western分析，Ang II增加了MAPK激酶抑制剂PD98059 （10 μM/L）阻断的MAPK和cpla2的磷酸化。同样，PI3K抑制剂LY294002 （10 μM/L）可以消除Ang ii介导的MAPK磷酸化和磷酸丝氨酸- pla2的增加。此外，抑制PI3K阻断了Ang ii诱导的AA释放和VSMC有丝分裂发生。然而，外源AA能够在LY294002存在的情况下恢复VSMC的生长，并逆转LY294002对MAPK和cpla2磷酸化的抑制。因此，从这些数据可以看出，Ang II刺激pi3k敏感的AA释放，从而刺激MAPK磷酸化cpla2，增强AA释放。这一机制可能在angii诱导的VSMC生长中起重要作用。
Angiotensin (Ang) II via the AT1receptor acts as a mitogen in vascular smooth muscle cells (VSMC) through stimulation of multiple signaling mechanisms, including tyrosine kinases and mitogen-activated protein kinase (MAPK). In addition, cytosolic phospholipase A2(cPLA2)-dependent release of arachidonic acid (AA) is linked to VSMC growth and we have reported that Ang II stimulates cPLA2activity via the AT1receptor. The coupling of Ang II to the activation of cPLA2appears to involve mechanisms both upstream and downstream of MAPK such that AA stimulates MAPK activity which phosphorylates cPLA2to further enhance AA release. However, the upstream mechanisms responsible for activation of cPLA2are not well-defined. One possibility includes phosphatidylinositide 3-kinase (PI3K), since PI3K has been reported to participate in the upstream signaling events linked to activation of MAPK. However, it is not known whether PI3K is involved in the Ang II-induced activation of cPLA2or if this mechanism is associated with the Ang II-mediated growth of VSMC. Therefore, we used cultured rat VSMC to examine the role of PI3K in the Ang II-dependent phosphorylation of cPLA2, release of AA, and growth induced by Ang II. Exposure of VSMC to Ang II (100 nM) increased [3H]thymidine incorporation, cell number, and the release of [3H]AA. Also, using Western analysis, Ang II increased the phosphorylation of MAPK and cPLA2which were blocked by the MAPK kinase inhibitor PD98059 (10 μM/L ) . Similarly, the PI3K inhibitor LY294002 (10 μM/L ) abolished the Ang II-mediated increase in MAPK phosphorylation, as well as phosphoserine-PLA2. Further, inhibition of PI3K blocked the Ang II-induced release of AA and VSMC mitogenesis. However, exogenous AA was able to restore VSMC growth in the presence of LY294002, as well as reverse the inhibition of MAPK and cPLA2phosphorylation by LY294002. Thus, it appears from these data that Ang II stimulates the PI3K-sensitive release of AA which stimulates MAPK to phosphorylate cPLA2and enhance AA release. This mechanism may play an important role in the Ang II-induced growth of VSMC.
影响因子：
8.3
作者：
Freeman, EJ;Chisolm, GM;Tallant, EA
通讯作者：
Tallant, EA
花生四烯酸诱导表皮生长因子受体酪氨酸磷酸化和 Shc-Grb2-Sos 关联。
DOI：
10.1161/01.hyp.32.6.1089
发表时间：
1998
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Dulin,NO;Sorokin,A;Douglas,JG
通讯作者：
Douglas,JG
血管紧张素II诱导牛肾上腺皮质细胞增殖的机制。
影响因子：
4.8
作者：
Natarajan,R;Gonzales,N;Hornsby,PJ;Nadler,J
通讯作者：
Nadler,J