雙特異性磷酸酶6在血管平滑肌細胞扮演的角色;The Role of Dual-specificity Phosphatase 6 in Vascular Smooth Muscle Cells

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Title:	雙特異性磷酸酶6在血管平滑肌細胞扮演的角色;The Role of Dual-specificity Phosphatase 6 in Vascular Smooth Muscle Cells
Authors:	禾汀;Hamdin, Candra Dwipayana
Contributors:	生命科學系
Keywords:	雙特異性磷酸酶 6;血管重塑;遷移;N-鈣黏蛋白;血管平滑肌細胞;增生;細胞週期素激酶抑制劑;DUSP6;vascular remodeling;migration;N-cadherin;VSMC;proliferation;p27
Date:	2024-01-12
Issue Date:	2024-09-19 15:22:05 (UTC+8)
Publisher:	國立中央大學
Abstract:	動脈壁的血管平滑肌細胞 (VSMC) 通常表現出分化的收縮表型；損傷後，VSMC 去分化為增生和遷移表型，導致內膜增生。細胞外訊號調節激酶 1/2 (ERK1/2) 參與 VSMC 增生和遷移。雙特異性磷酸酶 6 (DUSP6) 可以使活化的 ERK1/2 去磷酸化。我們的目標是研究 DUSP6 是否透過調節 VSMC 增殖和遷移而影響阻塞性血管疾病。利用小鼠內膜增生模型，我們發現正常未受傷的小鼠動脈的 DUSP6 基線水平較低，而損傷後該水平顯著升高。與野生型小鼠相比，DUSP6全身性缺陷 (Dusp6–/–) 小鼠的新內膜較小。在體外，IL-1β 誘導 DUSP6 表現並增加 VSMC 增生和遷移，而缺乏DUSP6會減少IL-1β誘導的VSMC增生和遷移。有趣的是，DUSP6 的缺乏並不影響 IL-1β 刺激後的 ERK1/2 磷酸化。 ERK1/2 抑制劑 U0126 抑制 IL-1β 誘導的DUSP6表現。這些數據顯示在VSMC中，ERK1/2作用在DUSP6上游調節DUSP6的表現量，而不是DUSP6下游之作用物。 IL-1β 降低 VSMC 中細胞週期抑制劑 p27 及與細胞遷移有關的細胞間黏附分子 N-鈣黏蛋白的表現量。有趣的是，即使在IL-1β刺激下缺乏 DUSP6 還是會維持p27 和 N-鈣粘蛋白在較高水平。這些數據揭示了 DUSP6 在調節 VSMC 中 p27 和 N-鈣粘蛋白表現量方面的新功能。綜上所述，我們的結果顯示，缺乏DUSP6 會透過減少 VSMC 增生和遷移來減低動脈損傷後的新內膜形成，這可能是透過維持高 p27 和 N-鈣黏蛋白水平而導至的。;Vascular smooth muscle cells (VSMCs) of the arterial wall normally exhibit a differentiated, contractile phenotype; upon injury, VSMCs dedifferentiate into a proliferative and migratory phenotype, leading to intimal hyperplasia. The extracellular signal-regulated kinase 1/2 (ERK1/2) participates in VSMC proliferation and migration. Dual-specificity phosphatase 6 (DUSP6) can dephosphorylate activated ERK1/2. Our goal was to investigate whether DUSP6 has a role in occlusive vascular disease by regulating VSMC proliferation and migration. Utilizing a mouse neointimal formation model, we showed that uninjured mouse arteries had low baseline protein level of DUSP6, which was significantly increased after injury. Compared with wild-type mice, DUSP6-deficient (Dusp6–/–) mice had smaller neointima. In vitro, IL-1β induced DUSP6 protein expression and increased VSMC proliferation and migration. Lack of DUSP6 decreased IL-1β-induced VSMC proliferation and migration. Intriguingly, lack of DUSP6 did not affect IL-1β-stimulated ERK1/2 phosphorylation. ERK1/2 inhibitor U0126 prevented DUSP6 induction by IL-1β. These data indicate that in VSMCs, ERK1/2 functions upstream of DUSP6 by regulating DUSP6 protein expression rather than downstream as a substrate of DUSP6. IL-1β decreased protein levels of cell cycle inhibitor p27 and cell-cell adhesion molecule N-cadherin in VSMCs. N-cadherin has been implicated in cellular migration. Interestingly, lack of DUSP6 maintained p27 and N-cadherin at high levels. These data reveal novel functions of DUSP6 in regulating p27 and N-cadherin protein levels in VSMCs. Taken together, our results indicate that lack of DUSP6 attenuated neointima formation following arterial injury by reducing VSMC proliferation and migration, which were likely mediated via maintaining high p27 and N-cadherin protein levels.
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