1 Department of Physiology, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.
2 Department of Medical Science, School of Medicine, Chungnam National University , Daejeon, Republic of Korea.
Antioxid Redox Signal. 2017 Aug 1;27(4):234-249. doi: 10.1089/ars.2016.6719. Epub 2017 May 24.
Mitochondrial dysfunction has emerged as a major contributing factor to endothelial dysfunction and vascular disease, but the key mechanisms underlying mitochondrial dysfunction-induced endothelial dysfunction remain to be elucidated. In this study, we aim at determining whether mitochondrial dysfunction in endothelial cells plays a key role in vascular disease, by examining the phenotype of endothelial-specific CR6-interacting factor 1 (CRIF1) knockout mice. We also used siRNA-mediated downregulation of CRIF1 gene in the endothelial cells to study about the in vitro pathophysiological underlying mechanisms.
Downregulation of CRIF1 in endothelial cells caused disturbances of mitochondrial oxidative phosphorylation complexes and membrane potential, leading to enhanced mitochondrial reactive oxygen species production. Gene silencing of CRIF1 results in decreased SIRT1 expression along with increased endothelial nitric oxide synthase (eNOS) acetylation, leading to reduced nitric oxide production both in vitro and in vivo. Endothelium-dependent vasorelaxation of aortic rings from CRIF1 knockout (KO) mice was considerably less than in wild-type mice, and it was partially recovered by Sirt1 overexpression in CRIF1 KO mice.
Our results show for the first time a relationship between mitochondrial dysfunction and impaired vascular function induced in CRIF1 deficiency conditions and also the possible underlying pathway involved.
These findings indicate that CRIF1 plays an important role in maintaining mitochondrial and endothelial function through its effects on the SIRT1-eNOS pathway. Antioxid. Redox Signal. 27, 234-249.
线粒体功能障碍已成为内皮功能障碍和血管疾病的主要致病因素，但线粒体功能障碍导致内皮功能障碍的关键机制仍有待阐明。在这项研究中，我们旨在通过检查内皮细胞特异性 CR6 相互作用因子 1（CRIF1）敲除小鼠的表型，确定内皮细胞中线粒体功能障碍是否在血管疾病中起关键作用。我们还使用内皮细胞中 siRNA 介导的 CRIF1 基因下调来研究体外病理生理潜在机制。
内皮细胞中 CRIF1 的下调导致线粒体氧化磷酸化复合物和膜电位紊乱，导致线粒体活性氧产生增加。CRIF1 的基因沉默导致 SIRT1 表达减少，同时内皮型一氧化氮合酶（eNOS）乙酰化增加，导致体外和体内一氧化氮产生减少。CRIF1 敲除（KO）小鼠主动脉环的内皮依赖性血管舒张明显小于野生型小鼠，而 CRIF1 KO 小鼠中 Sirt1 的过表达部分恢复了这种舒张。
我们的研究结果首次表明，在 CRIF1 缺乏条件下，线粒体功能障碍与血管功能受损之间存在关联，并且还涉及到可能的潜在途径。
这些发现表明，CRIF1 通过其对 SIRT1-eNOS 途径的影响，在维持线粒体和内皮功能方面发挥重要作用。抗氧化还原信号。27, 234-249.
