Histone deacetylase 6 reduction promotes aortic valve calcification via an endoplasmic reticulum stress-mediated osteogenic pathway
Histone deacetylase 6 reduction promotes aortic valve calcification via an endoplasmic reticulum stress-mediated osteogenic pathway
复制标题
组蛋白脱乙酰酶 6 减少通过内质网应激介导的成骨途径促进主动脉瓣钙化
DOI：
10.1016/j.jtcvs.2018.10.136
复制
发表时间：
2019-08-01
影响因子：
6
通讯作者：
Xiang, Meixiang
中科院分区：
文献类型：
--
作者：
Fu, Zurong;Li, Fei;Xiang, Meixiang
目的：主动脉瓣（AoV）钙化是一个病理生理过程，包括瓣间质细胞（VICs）的成骨分化。组蛋白去乙酰化酶（hdac）已被证明参与血管疾病的发病机制。在这里，我们研究了HDAC6在AoV钙化中的作用。方法：对主动脉瓣狭窄患者（n = 7）和正常人（n = 7）的AoV尖部进行钙化结节和HDAC6表达的检测。在成骨培养基中培养人vic，用10 μ m的tubacin或HDAC6小干扰RNA沉默处理以抑制HDAC6。100 μ m牛磺酸去氧胆酸可抑制内质网应激。激活转录因子4 （ATF4）小干扰RNA敲除ATF4。用茜素红染色观察成骨培养基培养14天的vic钙化结节形成情况。结果：与对照组相比，主动脉瓣狭窄患者AoV组织中HDAC6表达明显降低。Tubacin治疗或HDAC6沉默显著促进成骨细胞分化，并伴有内质网应激激活。通过牛磺酸去氧胆酸预处理或ATF4沉默提示HDAC6抑制诱导的成骨途径是内质网应激/ATF4途径介导的。最后，茜素红染色显示，抑制HDAC6可促进VICs成骨细胞分化，而牛磺酸去氧胆酸可抑制这种分化。结论：抑制HDAC6通过内质网应激/ atf4介导的成骨途径促进AoV钙化。HDAC6可能是预防和治疗AoV钙化的新靶点。
Objective: Aortic valve (AoV) calcification occurs via a pathophysiologic process that includes osteoblastic differentiation of valvular interstitial cells (VICs). Histone deacetylases (HDACs) have been shown to be involved in the pathogenesis of vascular diseases. Here, we investigated the role of HDAC6 in AoV calcification.Methods: AoV cusps from patients with aortic stenosis (n = 7) and normal controls (n = 7) were subjected to determination of calcified nodules and HDAC6 expression. Human VICs were cultured in osteogenic media and treated with 10 uM tubacin or HDAC6 small interfering RNA silencing to inhibit HDAC6. Treatment with 100 uM tauroursodeoxycholic acid was used to suppress endoplasmic reticulum stress. Activating transcription factor 4 (ATF4) small interfering RNA was used to knock down ATF4. Alizarin red staining was used to evaluate calcified nodules formation of VICs cultured with osteogenic media for 14 days.Results: HDAC6 expression was significantly reduced in AoV tissue of patients with aortic stenosis compared with controls. Tubacin treatment or HDAC6 silencing markedly promoted osteoblastic differentiation accompanied by endoplasmic reticulum stress activation in VICs. The HDAC6 inhibition-induced osteogenic pathway was mediated by endoplasmic reticulum stress/ATF4 pathway as indicated by tauroursodeoxycholic acid pretreatment or ATF4 silencing. Finally, alizarin red staining showed that HDAC6 inhibition promoted osteoblastic differentiation of VICs, which could be suppressed by tauroursodeoxycholic acid.Conclusions: HDAC6 inhibition promotes AoV calcification via an endoplasmic reticulum stress/ATF4-mediated osteogenic pathway. HDAC6 may be a novel target for AoV calcification prevention and treatment.