在靜脈移植手術中，當靜脈轉換於動脈的血流微環境時會誘導早期靜脈內皮細胞剝落及損傷以至於造成血管再窄化。近年來，已有文獻提出在動脈內皮細胞中，不同血流剪切力像是動脈層流剪切力（Arterial laminar shear stress, ALS）和震盪剪切 (Oscillatory shear, OS) 會透過去組蛋白乙醯酶(Histone deacetylases, HDACs) 和組蛋白3離氨酸9甲基化(H3K9 methylation)等表觀遺傳學(Epigenetic) 進而調控細胞週期和發炎反應。然而，HDAC3和H3K9me3是否參與調節動脈層流所導致的靜脈內皮細胞損傷目前還尚未清楚。因此我們假設動靜脈間血流剪切力轉換而導致不同HDACs以及H3K9me3的表現造成靜脈內皮細胞損傷。初步結果中，發現當動脈內皮細胞受到ALS刺激下會有高度表現H3K9me3並且促使細胞維持在G0時期。當靜脈內皮細胞處在ALS下則會改變其細胞型態呈現圓球狀以及H3K9me3 、HDAC3和HDAC5的低蛋白表現並增加發炎蛋白（VCAM-1）的表現。當在動脈內皮細胞中抑制HDAC表現時會導致發炎反應與細胞損失，其結果與ALS所引發的靜脈內皮細胞反應類似，同時觀察到藉由ITSA-1 (HDAC activator)活化HDAC的表現可以預防ALS所誘發之靜脈損傷。此外，已知粘著斑激酶 (Focal Adhesion Kinase, FAK)也參與在血流剪切力調控內皮細胞的型態，且在此研究中觀察到靜脈內皮細胞中加入ITSA-1會增加FAK磷酸化的活性以及當提高靜脈內皮細胞中FAK磷酸化表現時，亦可觀察到H3K9me3的表現增加。因此本篇研究中觀察到透過ITSA-1所增加H3K9me3以及HDAC的表現可以阻止靜脈移植病理的誘發。

A transition of flow microenvironments from vein to artery in vein graft surgery induces venous endothelial cell (vEC) peel-off in early stage and results in restenosis. Recently, different shear stresses (arterial laminar shear stress (ALS) and oscillatory shear (OS)) mediate the distinct cell cycle and inflammation through epigenetic controls like histone deacetylases (HDACs) and the methylation on lysine 9 of histone (H3K9) in arterial EC. Whether the roles of H3K9me3 and HDAC in vEC damage under ALS are still unknown. We hypothesized that the different response of HDACs and H3K9me3 might cause vEC damage under venous-arterial flow transition. We found that arterial EC showed increase of H3K9me3 expression and was kept in G0 phase after being subjected to ALS. Whereas, vEC showed round-up damage morphology under ALS with the decreases of H3K9me3, HDAC3, and HDAC5 and increase of vascular cell adhesion protein 1 (VCAM-1). Inhibition of HDACs activity by specific inhibitor in arterial EC caused similar ALS-induced inflammation and cell loss as vEC. In addition, activation of HDACs and H3K9me3 via ITSA-1in vEC could prevented the ALS-induced cell peel-off and reduced the VCAM-1 expression. Besides, shear stress modulates EC morphology by regulation of focal adhesion kinase (FAK). Our results also showed that ITSA-1 could increase p-FAK in vEC under ALS. We further perturbed the activity of p-FAK and found that the increase of p-FAK restored ALS-induced H3K9me3 in vEC. Therefore, we found that the abnormal mechanoresponses of H3K9me3 and HDAC in vEC after being subjected to ALS could be reversed by ITSA-1 treatment which prevented the vein graft pathogenesis.

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