LRP1 Repression by SNAIL Results in ECM Remodeling in Genetic Risk for Vascular Diseases

作者：Lu Liu, Joséphine Henry, Yingwei Liu, Charlène Jouve, Jean‐Sébastien Hulot, Adrien Georges, Nabila Bouatia‐Naji · 发表于：Circulation Research · 年份：2024 · DOI：10.1161/circresaha.124.325269 · 被引用次数：18 · 研究领域：Protease and Inhibitor Mechanisms、Connective Tissue Growth Factor Research、TGF-β signaling in diseases

BACKGROUND: Genome-wide association studies implicate common genetic variations in the LRP1 (low-density lipoprotein receptor-related protein 1 gene) locus at risk for multiple vascular diseases and traits. However, the underlying biological mechanisms are unknown. METHODS: Fine mapping analyses included Bayesian colocalization to identify the most likely causal variant. Human induced pluripotent stem cells were genome-edited using CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated protein 9) to delete or modify candidate enhancer regions and generate LRP1 knockout cell lines. Cells were differentiated into smooth muscle cells through a mesodermal lineage. Transcription regulation was assessed using luciferase reporter assay, transcription factor knockdown, and chromatin immunoprecipitation. Phenotype changes in cells were conducted using cellular assays, bulk RNA sequencing, and mass spectrometry. RESULTS: Multitrait colocalization analyses pointed at rs11172113 as the most likely causal variant in LRP1 for fibromuscular dysplasia, migraine, pulse pressure, and spontaneous coronary artery dissection. We found the rs11172113-T allele to associate with higher LRP1 expression. Genomic deletion in induced pluripotent stem cell–derived smooth muscle cells supported rs11172113 to locate in an enhancer region regulating LRP1 expression. We found transcription factors MECP2 (methyl CpG binding protein 2) and SNAIL (Zinc Finger Protein SNAI1) to ...