Greißel Anna, Culmes Mihaela, Burgkart Rainer, Zimmermann Alexander, Eckstein Hans-Henning, Zernecke Alma, Pelisek Jaroslav
Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Germany.
Clinic of Orthopedics, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Germany.
Cardiovasc Pathol. 2016 Mar-Apr;25(2):79-86. doi: 10.1016/j.carpath.2015.11.001. Epub 2015 Nov 9.
The aim of the study was to analyze histone acetylation, methylation, and the expression of their corresponding transferases in atherosclerotic plaques of patients with carotid artery stenosis.
Atherosclerotic tissue from our biobank (n=80) was divided into various segments covering all plaque stages and classified according to the American Heart Association. The plaques were assigned to early (types I-III) or advanced (types V-VII) stage group of atherosclerosis. Ten healthy carotid arteries from transplant donors served as controls. The expression of histone acetyltransferases (GNAT group: GCN5L, P300/CBP group: P300, MYST group: MYST1 and MYST2) and histone methyltransferases (H3K4: MLL2/4, SET7/9, and hSET1A; H3K9: SUV39H1, SUV39H2, ESET/SETDB1, and EHMT1; H3K27: EZH2 and G9a) was analyzed by SYBR-green-based real-time polymerase chain reaction. Histone acetylation/methylation in the cells within atherosclerotic plaques was determined by immunohistochemistry.
Increased histone acetylation was observed on H3K9 and H3K27 in smooth muscle cells (SMCs) in advanced atherosclerotic lesions compared to healthy vessels (P=.002 and .034). H3K9 acetylation in SMCs and macrophages was associated with plaque severity of atherosclerosis (P=.048 and <.001). Expression of GCN5L and MYST1 also correlated with the severity of atherosclerosis (P<.001). Methylation of H3K9 and H3K27 was significantly reduced in atherosclerotic plaques in SMCs and inflammatory cells (P<.001 and .026). Methylation on H3K4 was significantly associated with the severity of atherosclerosis. Expression of methyltransferase MLL2/4 was increased in advanced stages of atherosclerosis (P<.001).
Histone acetylation and methylation seem to play a decisive role in atherosclerosis, showing significant differences between healthy vessels and vessels at different stages of atherosclerosis.
本研究旨在分析颈动脉狭窄患者动脉粥样硬化斑块中组蛋白乙酰化、甲基化及其相应转移酶的表达情况。
从我们的生物样本库中获取动脉粥样硬化组织（n = 80），将其分为覆盖所有斑块阶段的不同节段，并根据美国心脏协会进行分类。这些斑块被分为动脉粥样硬化的早期（I - III型）或晚期（V - VII型）阶段组。来自移植供体的10条健康颈动脉作为对照。通过基于SYBR - green的实时聚合酶链反应分析组蛋白乙酰转移酶（GNAT组：GCN5L；P300/CBP组：P300；MYST组：MYST1和MYST2）和组蛋白甲基转移酶（H3K4：MLL2/4、SET7/9和hSET1A；H3K9：SUV39H1、SUV39H2、ESET/SETDB1和EHMT1；H3K27：EZH2和G9a）的表达。通过免疫组织化学法测定动脉粥样硬化斑块内细胞中的组蛋白乙酰化/甲基化情况。
与健康血管相比，在晚期动脉粥样硬化病变的平滑肌细胞（SMC）中，观察到H3K9和H3K27上的组蛋白乙酰化增加（P = 0.002和0.034）。SMC和巨噬细胞中H3K9乙酰化与动脉粥样硬化的斑块严重程度相关（P = 0.048和<0.001）。GCN5L和MYST1的表达也与动脉粥样硬化的严重程度相关（P < 0.001）。SMC和炎症细胞中动脉粥样硬化斑块内H3K9和H3K27的甲基化显著降低（P < 0.001和0.026）。H3K4甲基化与动脉粥样硬化的严重程度显著相关。甲基转移酶MLL2/4的表达在动脉粥样硬化晚期增加（P < 0.001）。
组蛋白乙酰化和甲基化似乎在动脉粥样硬化中起决定性作用，在健康血管和动脉粥样硬化不同阶段的血管之间显示出显著差异。
