Sox13 is a novel flow-sensitive transcription factor that prevents inflammation by repressing chemokine expression in endothelial cells

• DOI: 10.3389/fcvm.2022.979745
• Publication Date: 2022-09-30T06:20:40Z
• Authors: Catherine Demos; Janie Johnson; Aitor Andueza; Christian Park; Yerin Kim; Nicolas Villa-Roel; Dong-Won Kang; Sandeep Kumar; Hanjoong Jo
• Keywords: 0301 basic medicine; Sox13; 03 medical and health sciences; CCL5; endothelium; inflammation; CXCL10; RC666-701; Diseases of the circulatory (Cardiovascular) system; Cardiovascular Medicine; shear-sensitive TF

Atherosclerosis is a chronic inflammatory disease and occurs preferentially in arterial regions exposed to disturbed blood flow (d-flow) while the stable (s-flow) are spared. D-flow induces endothelial inflammation atherosclerosis by regulating gene expression partly through flow-sensitive transcription factors (FSTFs). Most FSTFs, including well-known Kruppel-like KLF2 KLF4, have been identified from vitro studies using cultured cells (ECs). Since many genes pathways lost or dysregulated ECs during culture, we hypothesized that important FSTFs vivo not identified. We tested hypothesis analyzing our recent array single-cell RNA sequencing (scRNAseq) chromatin accessibility (scATACseq) datasets generated mouse partial carotid ligation model. From analyses, 30 expected KLF2/4 novel FSTFs. They were further validated arteries human aortic (HAECs). These results revealed 8 SOX4, SOX13, SIX2, ZBTB46, CEBPβ, NFIL3, KLF2, conserved mice humans vitro. selected SOX13 for because of its robust regulation, preferential ECs, unknown flow-dependent function. found siRNA-mediated knockdown increased responses even under unidirectional laminar shear stress (ULS, mimicking s-flow) condition. To understand underlying mechanisms, conducted an RNAseq study HAECs treated with siRNA conditions (ULS vs. oscillatory d-flow). 94 downregulated 40 upregulated changed shear- SOX13-dependent manner. Several cytokines, CXCL10 CCL5, most strongly siRNA. The induction CCL5 was qPCR ELISA HAECs. Moreover, treatment Met-CCL5, specific receptor antagonist, prevented induced siSOX13. In addition, overexpression responses. summary, FSTF, which represses pro-inflammatory chemokines s-flow. Reduction triggers chemokine responses, major proatherogenic pathway.