Inhibition of Mitogen Activated Protein Kinase Activated Protein Kinase II with MMI-0100 reduces intimal hyperplasia ex vivo and in vivo.
Inhibition of Mitogen Activated Protein Kinase Activated Protein Kinase II with MMI-0100 reduces intimal hyperplasia ex vivo and in vivo.
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DOI：
10.1016/j.vph.2011.07.008
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发表时间：
2012-01
影响因子：
4
通讯作者：
Dardik, Alan
中科院分区：
文献类型：
--
作者：
Muto, Akihito;Panitch, Alyssa;Kim, Namho;Park, Kinam;Komalavilas, Padmini;Brophy, Colleen M.;Dardik, Alan
静脉移植物内膜增生仍然是移植失败的主要原因，尽管许多药理学方法未能转化为人类治疗。我们研究了MMI-0100（一种新的丝裂原活化蛋白激酶活化蛋白激酶II（MK2）的肽抑制剂）局部抑制炎症和纤维化是否是减少细胞增殖和内膜增生的替代策略。使用标准Fmoc化学合成细胞渗透性肽MMI-0100。药理学剂量的MMI-0100诱导最小的人内皮细胞和平滑肌细胞增殖（分别为30%和12%）。MMI-0100将IL-6表达抑制至对照水平，而对IL-8表达没有影响。MMI-0100以剂量依赖性方式引起硝普钠诱导的人隐静脉环平滑肌细胞松弛并抑制内膜增厚。在鼠主动脉旁路模型中，MMI-0100使静脉移植物中的内膜厚度减少72%，并且在用MMI-0100处理的静脉移植物中存在较少的F4/80反应性细胞。MMI-0100可预防离体和体内静脉移植物内膜增厚。这些结果表明，用细胞渗透肽MMI-0100抑制MK2可能是抑制纤维化过程如静脉移植物疾病的新策略。
Vein graft intimal hyperplasia remains the leading cause of graft failure, despite many pharmacological approaches that have failed to translate to human therapy. We investigated whether local suppression of inflammation and fibrosis with MMI-0100, a novel peptide inhibitor of Mitogen Activated Protein Kinase Activated Protein Kinase II (MK2), would be an alternative strategy to reduce cell proliferation and intimal hyperplasia. The cell permeable peptide MMI-0100 was synthesized using standard Fmoc chemistry. Pharmacological doses of MMI-0100 induced minimal human endothelial and smooth muscle cell proliferation (30% and 12% respectively). MMI-0100 suppressed IL-6 expression to control levels, without effect on IL-8 expression. MMI-0100 caused sodium nitroprusside induced smooth muscle cell relaxation and inhibited intimal thickening in human saphenous vein rings in a dose-dependent fashion. In a murine aortic bypass model, MMI-0100 reduced intimal thickness in vein grafts by 72%, and there were fewer F4/80-reactive cells in vein grafts treated with MMI-0100. MMI-0100 prevents vein graft intimal thickening ex vivo and in vivo. These results suggest that inhibition of MK2 with the cell-permeant peptide MMI-0100 may be a novel strategy to suppress fibrotic processes such as vein graft disease.
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影响因子：
6.5
作者：
Funding, Anne T.;Johansen, Claus;Iversen, Lars
通讯作者：
Iversen, Lars
影响因子：
2.2
作者：
KLYACHKIN, ML;DAVIES, MG;HAGEN, PO
通讯作者：
HAGEN, PO
影响因子：
5.3
作者：
Kotlyarov, A;Yannoni, Y;Gaestel, M
通讯作者：
Gaestel, M
DOI：
10.1016/j.bbrc.2009.03.056
发表时间：
2009-05-08
影响因子：
3.1
作者：
Lopes, Luciana B.;Flynn, Charles;Seal, Brandon L.
通讯作者：
Seal, Brandon L.
影响因子：
5.3
作者：
Epstein, H.;Grad, E.;Danenberg, H. D.
通讯作者：
Danenberg, H. D.