Aorta smooth muscle-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease.
Aorta smooth muscle-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease.
复制标题
主动脉平滑肌芯片揭示线粒体动力学受损可作为二叶式主动脉瓣疾病主动脉瘤的治疗靶点
DOI：
10.7554/elife.69310
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发表时间：
2021-09-06
期刊：
影响因子：
7.7
通讯作者：
Zhang W
中科院分区：
文献类型：
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作者：
Abudupataer M;Zhu S;Yan S;Xu K;Zhang J;Luo S;Ma W;Alam MF;Tang Y;Huang H;Chen N;Wang L;Yan G;Li J;Lai H;Wang C;Zhu K;Zhang W
背景资料：二叶式主动脉瓣（BAV）是普通人群中最常见的先天性心血管疾病，常与胸主动脉瘤（TAA）的发生相关。由于对发病机制的不完全理解，没有有效的策略来干预TAA进展。NOTCH 1表达不足与BAV-TAA高度相关，但其潜在机制仍有待阐明。方法：采用比较蛋白质组学方法分析BAV-TAA主动脉组织与正常主动脉组织的生物学差异。构建了基于微流控技术的主动脉平滑肌芯片模型，以评价NOTCH 1缺陷对人主动脉平滑肌细胞（HAoSMCs）收缩表型和线粒体动力学的影响。结果：人主动脉组织蛋白质分析显示BAV-TAA中NOTCH 1表达不足，线粒体动力学受损。NOTCH 1敲低的HAoSMC表现出收缩表型减少，并伴有线粒体融合减弱。此外，我们发现线粒体融合激活剂（来氟米特和特立氟胺）或线粒体裂变抑制剂（Mdivi-1）部分挽救了来自BAV-TAA患者的HAoSMC中的线粒体动力学障碍。结论：主动脉平滑肌芯片模型模拟了人体主动脉生物力学的病理生理参数，为主动脉疾病的分子机制研究和相关药物筛选提供了平台。这种主动脉平滑肌芯片模型和人类组织蛋白质组学分析表明，受损的线粒体动力学可能是BAV-TAA的潜在治疗靶点。资金来源：国家重点研发计划、国家自然科学基金、上海市科技重大专项、上海市科委、上海市教委。
Background: Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified. Methods: A comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta smooth muscle-on-a-chip model was constructed to evaluate the effect of NOTCH1 deficiency on contractile phenotype and mitochondrial dynamics of human aortic smooth muscle cells (HAoSMCs). Results: Protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) partially rescued the disorders of mitochondrial dynamics in HAoSMCs derived from BAV-TAA patients. Conclusions: The aorta smooth muscle-on-a-chip model simulates the human pathophysiological parameters of aorta biomechanics and provides a platform for molecular mechanism studies of aortic disease and related drug screening. This aorta smooth muscle-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA. Funding: National Key R and D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Commission, and Shanghai Municipal Education Commission.