Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors.
Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors.
复制标题
DOI：
10.1242/dmm.024513
复制
发表时间：
2016-05-01
影响因子：
4.3
通讯作者：
Rodriguez C
中科院分区：
文献类型：
--
作者：
Galán M;Varona S;Orriols M;Rodríguez JA;Aguiló S;Dilmé J;Camacho M;Martínez-González J;Rodriguez C
腹主动脉瘤（AAA）的临床管理目前仅限于择期手术修复，因为仍在等待有效的药物治疗。抑制组蛋白去乙酰化酶（HDAC）活性可能是心血管疾病的一种有前途的治疗选择。我们的目的是研究HDAC在人AAA中的表达，并评估I类和IIa类HDAC抑制剂在血管紧张素II（Ang II）输注载脂蛋白E缺陷（ApoE−/−）小鼠AAA模型中的治疗潜力。实时PCR、蛋白质印迹和免疫组织化学证实，与来自供体的腹主动脉样本（n=14）相比，来自接受AAA开放修复的患者（n=22）的腹主动脉样本中HDAC 1、2（均为I类）、4和7（均为IIa类）的表达增加。Ang-II输注ApoE−/−小鼠的主动脉瘤表现出相似的HDAC表达谱。在这些动物中，用I类HDAC抑制剂（MS-275）或IIa类抑制剂（MC-1568）治疗改善了存活率，降低了AAA的发生率和严重程度，并通过多普勒超声检查评估了有限的动脉瘤扩张。这些有益作用在MC-1568处理的小鼠中更有效。两种抑制剂均能有效地减少弹性蛋白和胶原纤维的解体以及淋巴细胞和巨噬细胞的浸润。此外，HDAC抑制减弱了该模型中由Ang II诱导的促炎标志物的加重表达和金属蛋白酶-2和-9活性的增加。因此，我们的数据证明HDAC表达在人AAA中失调，并且类别选择性HDAC抑制剂限制AAA小鼠模型中的动脉瘤扩张。新一代HDAC抑制剂代表了克服人类动脉瘤进展的有前景的治疗方法。总结：本研究报告了HDAC在人AAA中的上调，证明HDAC抑制剂在临床前模型中限制动脉瘤进展，并表明HDAC抑制在AAA中的治疗意义。
Clinical management of abdominal aortic aneurysm (AAA) is currently limited to elective surgical repair because an effective pharmacotherapy is still awaited. Inhibition of histone deacetylase (HDAC) activity could be a promising therapeutic option in cardiovascular diseases. We aimed to characterise HDAC expression in human AAA and to evaluate the therapeutic potential of class I and IIa HDAC inhibitors in the AAA model of angiotensin II (Ang II)-infused apolipoprotein-E-deficient (ApoE−/−) mice. Real-time PCR, western blot and immunohistochemistry evidenced an increased expression of HDACs 1, 2 (both class I), 4 and 7 (both class IIa) in abdominal aorta samples from patients undergoing AAA open repair (n=22) compared with those from donors (n=14). Aortic aneurysms from Ang-II-infused ApoE−/− mice exhibited a similar HDAC expression profile. In these animals, treatment with a class I HDAC inhibitor (MS-275) or a class IIa inhibitor (MC-1568) improved survival, reduced the incidence and severity of AAA and limited aneurysmal expansion evaluated by Doppler ultrasonography. These beneficial effects were more potent in MC-1568-treated mice. The disorganisation of elastin and collagen fibres and lymphocyte and macrophage infiltration were effectively reduced by both inhibitors. Additionally, HDAC inhibition attenuated the exacerbated expression of pro-inflammatory markers and the increase in metalloproteinase-2 and -9 activity induced by Ang II in this model. Therefore, our data evidence that HDAC expression is deregulated in human AAA and that class-selective HDAC inhibitors limit aneurysm expansion in an AAA mouse model. New-generation HDAC inhibitors represent a promising therapeutic approach to overcome human aneurysm progression. Summary: This study reports the upregulation of HDACs in human AAA, evidences that HDAC inhibitors limit aneurysm progression in a preclinical model and suggests the therapeutic interest of HDAC inhibition in AAA.