Han Yanshuo, Tanios Fadwa, Reeps Christian, Zhang Jian, Schwamborn Kristina, Eckstein Hans-Henning, Zernecke Alma, Pelisek Jaroslav
Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar der Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
Department of Vascular and Surgery, The First Hospital of China Medical University, Shenyang, China.
Clin Epigenetics. 2016 Jan 13;8:3. doi: 10.1186/s13148-016-0169-6. eCollection 2016.
Epigenetic modifications may play a relevant role in the pathogenesis of human abdominal aortic aneurysm (AAA). The aim of the study was therefore to investigate histone acetylation and expression of corresponding lysine [K] histone acetyltransferases (KATs) in AAA.
A comparative study of AAA tissue samples (n = 37, open surgical intervention) and healthy aortae (n = 12, trauma surgery) was performed using quantitative PCR, immunohistochemistry (IHC), and Western blot. Expression of the KAT families GNAT (KAT2A, KAT2B), p300/CBP (KAT3A, KAT3B), and MYST (KAT5, KAT6A, KAT6B, KAT7, KAT8) was significantly higher in AAA than in controls (P ≤ 0.019). Highest expression was observed for KAT2B, KAT3A, KAT3B, and KAT6B (P ≤ 0.007). Expression of KAT2B significantly correlated with KAT3A, KAT3B, and KAT6B (r = 0.705, 0.564, and 0.528, respectively, P < 0.001), and KAT6B with KAT3A, KAT3B, and KAT6A (r = 0.407, 0.500, and 0.531, respectively, P < 0.05). Localization of highly expressed KAT2B, KAT3B, and KAT6B was further characterized by immunostaining. Significant correlations were observed between KAT2B with endothelial cells (ECs) (r = 0.486, P < 0.01), KAT3B with T cells and macrophages, (r = 0.421 and r = 0.351, respectively, P < 0.05), KAT6A with intramural ECs (r = 0.541, P < 0.001) and with a contractile phenotype of smooth muscle cells (SMCs) (r = 0.425, P < 0.01), and KAT6B with T cells (r = 0.553, P < 0.001). Furthermore, KAT2B was associated with AAA diameter (r = 0.382, P < 0.05), and KAT3B, KAT6A, and KAT6B correlated negatively with blood urea nitrogen (r = -0.403, -0.408, -0.478, P < 0.05). In addtion, acetylation of the histone substrates H3K9, H3K18 and H3K14 was increased in AAA compared to control aortae.
Our results demonstrate that aberrant epigenetic modifications such as changes in the expression of KATs and acetylation of corresponding histones are present in AAA. These findings may provide new insight in the pathomechanism of AAA.
表观遗传修饰可能在人类腹主动脉瘤（AAA）的发病机制中起相关作用。因此，本研究的目的是调查AAA中组蛋白乙酰化及相应赖氨酸[K]组蛋白乙酰转移酶（KATs）的表达情况。
使用定量PCR、免疫组织化学（IHC）和蛋白质印迹法对AAA组织样本（n = 37，开放手术干预）和健康主动脉（n = 12，创伤手术）进行了比较研究。AAA中KAT家族GNAT（KAT2A、KAT2B）、p300/CBP（KAT3A、KAT3B）和MYST（KAT5、KAT6A、KAT6B、KAT7、KAT8）的表达显著高于对照组（P≤0.019）。观察到KAT2B、KAT3A、KAT3B和KAT6B的表达最高（P≤0.007）。KAT2B的表达与KAT3A、KAT3B和KAT6B显著相关（r分别为0.705、0.564和0.528，P<0.001），KAT6B与KAT3A、KAT3B和KAT6A显著相关（r分别为0.407、0.500和0.531，P<0.05）。通过免疫染色进一步对高表达的KAT2B、KAT3B和KAT6B进行定位。观察到KAT2B与内皮细胞（ECs）显著相关（r = 0.486，P<0.01），KAT3B与T细胞和巨噬细胞显著相关（r分别为0.421和0.351，P<0.05），KAT6A与壁内ECs显著相关（r = 0.541，P<0.001）且与平滑肌细胞（SMCs）的收缩表型显著相关（r = 0.425，P<0.01），KAT6B与T细胞显著相关（r = 0.553，P<0.001）。此外，KAT2B与AAA直径相关（r = 0.38
2，P<0.05），KAT3B、KAT6A和KAT6B与血尿素氮呈负相关（r分别为-0.403、-0.408、-0.478，P<0.05）。此外，与对照主动脉相比，AAA中组蛋白底物H3K9、H3K18和H3K14的乙酰化增加。
我们的结果表明，AAA中存在异常的表观遗传修饰，如KATs表达变化和相应组蛋白的乙酰化。这些发现可能为AAA的发病机制提供新的见解。
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