Temporal PTEN inactivation causes proliferation of saphenous vein smooth muscle cells of human CABG conduits.
Temporal PTEN inactivation causes proliferation of saphenous vein smooth muscle cells of human CABG conduits.
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DOI：
10.1111/j.1582-4934.2008.00311.x
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发表时间：
2009-01
影响因子：
5.3
通讯作者：
Agrawal DK
中科院分区：
文献类型：
--
作者：
Mitra AK;Jia G;Gangahar DM;Agrawal DK
内乳动脉（IMA）冠状动脉旁路移植物（CABG）与隐静脉（SV）移植物相比，在冠状动脉-冠状动脉吻合后，对内膜增生（IH）有显著的抵抗作用。这种令人费解的差异背后的原因仍然是一个谜。在这项研究中，我们研究了IGF-1刺激对PI 3 K-AKT/PKB通路介导IMA和SV来源的平滑肌细胞（SMC）增殖的影响，以及在这些条件下磷酸酶和张力蛋白同源物（PTEN）在调节IGF-1-PI 3 K-AKT/PKB轴中的特异性贡献。IGF-1的促有丝分裂激活作用时间依赖性地刺激SV SMC中PI 3 K和AKT/PKB的磷酸化程度比IMA大得多。相反，发现PTEN在IMA SMC中显著更活跃。在SV和IMA的SMC中瞬时过表达PTEN可抑制AKT/PKB及其上游的活性，导致IGF-1受体减少。下游，SV SMC中的PTEN过表达通过下调其抑制剂MDM 2的表达诱导肿瘤抑制蛋白p53的反式激活。然而，PTEN过表达对IMA SMC中MDM 2和p53的表达没有显著影响。在SV和IMA中，PTEN过表达抑制IGF-1诱导的SMC增殖。通过IMA SMC的siRNA转染诱导的PTEN抑制减少了PI 3 K-PKB信号传导的负调节，导致由IGF-1刺激诱导的更大的增殖反应。因此，我们第一次表明，在SV SMC中的PTEN的早期失活导致促增生PI 3 K-AKT/PKB途径的活性暂时增加，从而导致IH诱导的静脉移植物闭塞。因此，通过PTEN调节PI 3 K-AKT/PKB通路可能是对抗CABG后SV移植物衰竭的一种新的有效策略。
Internal mammary artery (IMA) coronary artery bypass grafts (CABG) are remarkably resistant to intimal hyperplasia (IH) as compared to saphenous vein (SV) grafts following aorto-coronary anastomosis. The reason behind this puzzling difference still remains an enigma. In this study, we examined the effects of IGF-1 stimulation on the PI3K-AKT/PKB pathway mediating proliferation of smooth muscle cells (SMCs) of IMA and SV origin and the specific contribution of phosphatase and tensin homologue (PTEN) in regulating the IGF-1-PI3K-AKT/PKB axis under these conditions. Mitogenic activation with IGF-1, time-dependently stimulated the phosphorylation of PI3K and AKT/PKB in the SV SMCs to a much greater extent than the IMA. Conversely, PTEN was found to be significantly more active in IMA SMCs. Transient overexpression of PTEN in SMCs of SV and IMA inhibited AKT/PKB activity and upstream of AKT/PKB, caused a reduction of IGF-1 receptors. Downstream, PTEN overexpression in SV SMCs induced the transactivation of tumour suppressor protein p53 by down-regulating the expression of its inhibitor MDM2. However, PTEN overexpression had no significant effect on MDM2 and p53 expression in IMA SMCs. PTEN overexpression inhibited IGF-1-induced SMC proliferation in both SV and IMA. PTEN suppression, induced by siRNA transfection of IMA SMCs diminished the negative regulation of PI3K-PKB signalling leading to greater proliferative response induced by IGF-1 stimulation. Thus, we show for the first time that early inactivation of PTEN in SV SMCs leads to temporally increased activity of the pro-hyperplasia PI3K-AKT/PKB pathway leading to IH-induced vein graft occlusion. Therefore, modulation of the PI3K-AKT/PKB pathway via PTEN might be a novel and effective strategy in combating SV graft failure following CABG.
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DOI：
10.1016/j.jtcvs.2004.11.048
发表时间：
2005-06-01
影响因子：
6
作者：
Hata, JA;Petrofski, JA;Milano, CA
通讯作者：
Milano, CA
DOI：
10.1016/0735-1097(96)00206-9
发表时间：
1996-09-01
影响因子：
24
作者：
FitzGibbon, GM;Kafka, HP;Burton, JR
通讯作者：
Burton, JR
影响因子：
4.8
作者：
Gesbert, F;Sellers, WR;Griffin, JD
通讯作者：
Griffin, JD
影响因子：
4.3
作者：
Dhume, AS;Agrawal, DK
通讯作者：
Agrawal, DK
影响因子：
8.7
作者：
Higaki, M;Shimokado, K
通讯作者：
Shimokado, K