Plumericin inhibits proliferation of vascular smooth muscle cells by blocking STAT3 signaling via S-glutathionylation.
Plumericin inhibits proliferation of vascular smooth muscle cells by blocking STAT3 signaling via S-glutathionylation.
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DOI：
10.1038/srep20771
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发表时间：
2016-02-09
影响因子：
4.6
通讯作者：
Dirsch VM
中科院分区：
文献类型：
--
作者：
Heiss EH;Liu R;Waltenberger B;Khan S;Schachner D;Kollmann P;Zimmermann K;Cabaravdic M;Uhrin P;Stuppner H;Breuss JM;Atanasov AG;Dirsch VM
动脉粥样硬化和再狭窄的病因涉及异常炎症和增殖，使得具有抗炎和抗有丝分裂特性的化合物成为对抗血管疾病的有希望的候选物。最近的一项研究发现环烯醚萜苷、鸡蛋花素是内皮细胞中促炎 NF-κB 通路的新型支架抑制剂。我们在这里检查了鸡蛋花素对原代血管平滑肌细胞（VSMC）增殖的影响。 Plummericin 抑制血清刺激的大鼠 VSMC 增殖。它使 VSMC 停滞在细胞周期的 G1/G0 期，同时消除细胞周期蛋白 D1 的表达，并阻碍视网膜母细胞瘤蛋白的 Ser 807/811 磷酸化。亲电性鸡蛋花素短暂消耗谷胱甘肽会导致 S-谷胱甘肽化，并阻碍 Tyr705-磷酸化以及转录因子信号转导器和转录激活子 3 (Stat3) 的激活。外源添加谷胱甘肽显着阻止了鸡蛋花素对 Stat3 的抑制作用。它还克服了细胞周期蛋白 D1 表达的下调和血清暴露后生物量增加的减少。这项研究揭示了鸡蛋花素对 VSMC 的抗增殖特性，这取决于鸡蛋花素的硫醇反应性和 Stat3 的 S-谷胱甘肽化。因此，鸡蛋花素通过针对血管功能障碍的至少两个罪魁祸首——炎症和平滑肌细胞增殖——可能成为一种有前途的用于血管疾病治疗的亲电先导化合物。
The etiology of atherosclerosis and restenosis involves aberrant inflammation and proliferation, rendering compounds with both anti-inflammatory and anti-mitogenic properties as promising candidates for combatting vascular diseases. A recent study identified the iridoid plumericin as a new scaffold inhibitor of the pro-inflammatory NF-κB pathway in endothelial cells. We here examined the impact of plumericin on the proliferation of primary vascular smooth muscle cells (VSMC). Plumericin inhibited serum-stimulated proliferation of rat VSMC. It arrested VSMC in the G1/G0-phase of the cell cycle accompanied by abrogated cyclin D1 expression and hindered Ser 807/811-phosphorylation of retinoblastoma protein. Transient depletion of glutathione by the electrophilic plumericin led to S-glutathionylation as well as hampered Tyr705-phosphorylation and activation of the transcription factor signal transducer and activator of transcription 3 (Stat3). Exogenous addition of glutathione markedly prevented this inhibitory effect of plumericin on Stat3. It also overcame downregulation of cyclin D1 expression and the reduction of biomass increase upon serum exposure. This study revealed an anti-proliferative property of plumericin towards VSMC which depends on plumericin’s thiol reactivity and S-glutathionylation of Stat3. Hence, plumericin, by targeting at least two culprits of vascular dysfunction –inflammation and smooth muscle cell proliferation -might become a promising electrophilic lead compound for vascular disease therapy.