Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT.
Department of Biology, University of Padua, Padua, Italy.
J Cell Biol. 2022 Jul 4;221(7). doi: 10.1083/jcb.202109144. Epub 2022 Jun 13.
Atherosclerosis, the major cause of myocardial infarction and stroke, results from converging inflammatory, metabolic, and biomechanical factors. Arterial lesions form at sites of low and disturbed blood flow but are suppressed by high laminar shear stress (LSS) mainly via transcriptional induction of the anti-inflammatory transcription factor, Kruppel-like factor 2 (Klf2). We therefore performed a whole genome CRISPR-Cas9 screen to identify genes required for LSS induction of Klf2. Subsequent mechanistic investigation revealed that LSS induces Klf2 via activation of both a MEKK2/3-MEK5-ERK5 kinase module and mitochondrial metabolism. Mitochondrial calcium and ROS signaling regulate assembly of a mitophagy- and p62-dependent scaffolding complex that amplifies MEKK-MEK5-ERK5 signaling. Blocking the mitochondrial pathway in vivo reduces expression of KLF2-dependent genes such as eNOS and inhibits vascular remodeling. Failure to activate the mitochondrial pathway limits Klf2 expression in regions of disturbed flow. This work thus defines a connection between metabolism and vascular inflammation that provides a new framework for understanding and developing treatments for vascular disease.
动脉粥样硬化是心肌梗死和中风的主要病因，它是由炎症、代谢和生物力学等多种因素共同作用的结果。动脉病变发生在血流缓慢和紊乱的部位，但高层流剪切应力（LSS）主要通过转录诱导抗炎转录因子 Kruppel 样因子 2（Klf2）来抑制病变的形成。因此，我们进行了全基因组 CRISPR-Cas9 筛选，以鉴定 Klf2 的 LSS 诱导所需的基因。随后的机制研究表明，LSS 通过激活 MEKK2/3-MEK5-ERK5 激酶模块和线粒体代谢来诱导 Klf2。线粒体钙和 ROS 信号调节依赖于线粒体自噬和 p62 的支架组装复合物的组装，该复合物可放大 MEKK-MEK5-ERK5 信号。体内阻断线粒体途径会降低 KLF2 依赖性基因（如 eNOS）的表达并抑制血管重塑。线粒体途径的激活失败会限制紊乱血流区域 Klf2 的表达。这项工作因此定义了代谢和血管炎症之间的联系，为理解和开发血管疾病的治疗方法提供了新的框架。
