Inhibition of Egr1 expression underlies the anti-mitogenic effects of cAMP in vascular smooth muscle cells.
Inhibition of Egr1 expression underlies the anti-mitogenic effects of cAMP in vascular smooth muscle cells.
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DOI：
10.1016/j.yjmcc.2014.02.001
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发表时间：
2014-07
影响因子：
5
通讯作者：
Bond, Mark
中科院分区：
文献类型：
--
作者：
Kimura, Tomomi E.;Duggirala, Aparna;Hindmarch, Charles C. T.;Hewer, Richard C.;Cui, Mei-Zhen;Newby, Andrew C.;Bond, Mark
关键词：
环磷酸腺苷抑制血管平滑肌细胞 (VSMC) 增殖，这在许多血管疾病的病因学中很重要。 VSMC 中 cAMP 的抗有丝分裂特性依赖于蛋白激酶 A (PKA) 的激活和 cAMP 激活的交换蛋白 (EPAC)，但其机制尚不清楚。 PKA 和 EPAC 的选择性激动剂协同抑制 Egr1 表达，这对于 VSMC 增殖至关重要。毛喉素、腺苷、A2B 受体激动剂 BAY60-6583 和西卡前列素也抑制 VSMC 中的 Egr1 表达，但不抑制内皮细胞中的 Egr1 表达。 cAMP 对 Egr1 的抑制不依赖于 cAMP 反应元件结合蛋白 (CREB) 活性，但依赖于血清反应元件 (SRE) 活性的抑制。 SRF 与 Egr1 启动子的结合不受 cAMP 刺激的调节。然而，Egr1 表达依赖于 SRF 辅助因子 Elk1 和 4，但不依赖于 MAL。 SRE 依赖性 Egr1 表达的抑制是由于 PKA 和 EPAC 对 Rac1 活性的协同抑制，导致细胞骨架快速重塑和 ERK1/2 的核输出。这与 SRF 辅因子 Elk1 的去磷酸化有关。 cAMP 通过快速抑制 Egr1 表达来抑制 VSMC 增殖。这种情况至少部分是通过抑制 Rac1 活性导致肌动蛋白细胞骨架快速重塑、ERK1/2 核输出、Elk1 磷酸化受损和 SRE 活性抑制而发生的。这确定了 cAMP 在 VSMC 中而非内皮细胞中抗有丝分裂作用的最早机制之一，使其成为选择性抑制 VSMC 增殖的有吸引力的靶点。 cAMP 通过快速抑制 Egr1 表达来抑制 VSMC 增殖。 PKA 和 Epac 协同抑制 Egr1 表达。 cAMP 介导的 Egr1 抑制具有细胞类型特异性。 cAMP 抑制 SRE 依赖性 Egr1 转录。 cAMP 通过 ERK1/2 的核输出和 Elk1 的去磷酸化来抑制 Egr1。
Cyclic AMP inhibits vascular smooth muscle cell (VSMC) proliferation which is important in the aetiology of numerous vascular diseases. The anti-mitogenic properties of cAMP in VSMC are dependent on activation of protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), but the mechanisms are unclear. Selective agonists of PKA and EPAC synergistically inhibited Egr1 expression, which was essential for VSMC proliferation. Forskolin, adenosine, A2B receptor agonist BAY60-6583 and Cicaprost also inhibited Egr1 expression in VSMC but not in endothelial cells. Inhibition of Egr1 by cAMP was independent of cAMP response element binding protein (CREB) activity but dependent on inhibition of serum response element (SRE) activity. SRF binding to the Egr1 promoter was not modulated by cAMP stimulation. However, Egr1 expression was dependent on the SRF co-factors Elk1 and 4 but independent of MAL. Inhibition of SRE-dependent Egr1 expression was due to synergistic inhibition of Rac1 activity by PKA and EPAC, resulting in rapid cytoskeleton remodelling and nuclear export of ERK1/2. This was associated with de-phosphorylation of the SRF co-factor Elk1. cAMP inhibits VSMC proliferation by rapidly inhibiting Egr1 expression. This occurs, at least in part, via inhibition of Rac1 activity leading to rapid actin-cytoskeleton remodelling, nuclear export of ERK1/2, impaired Elk1-phosphorylation and inhibition of SRE activity. This identifies one of the earliest mechanisms underlying the anti-mitogenic effects of cAMP in VSMC but not in endothelial cells, making it an attractive target for selective inhibition of VSMC proliferation. cAMP inhibits VSMC proliferation by rapidly inhibiting Egr1 expression. PKA and Epac synergise to inhibit Egr1 expression. cAMP-mediated inhibition of Egr1 is cell-type specific. cAMP inhibits SRE-dependent Egr1 transcription. cAMP inhibits Egr1 via nuclear export of ERK1/2 and de-phosphorylation of Elk1.
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DOI：
10.1161/01.atv.0000214980.90567.b5
发表时间：
2006-05-01
影响因子：
8.7
作者：
Cui, MZ;Laag, E;Xu, XM
通讯作者：
Xu, XM
DOI：
10.1073/pnas.90.21.10300
发表时间：
1993-11-01
影响因子：
11.1
作者：
GRAVES, LM;BORNFELDT, KE;KREBS, EG
通讯作者：
KREBS, EG
影响因子：
64.5
作者：
Sotiropoulos, A;Gineitis, D;Treisman, R
通讯作者：
Treisman, R
影响因子：
4.8
作者：
Tarcic, Gabi;Avraham, Roi;Yarden, Yosef
通讯作者：
Yarden, Yosef
影响因子：
3.3
作者：
Posern, G;Sotiropoulos, A;Treisman, R
通讯作者：
Treisman, R