表达数量性状基因座
细胞外基质
全基因组关联研究
表型
疾病
发病机制
血管平滑肌
基因座(遗传学)
基因表达谱
数量性状位点
基因表达
病理
细胞生物学
生物
基因
遗传学
医学
单核苷酸多态性
平滑肌
免疫学
内分泌学
基因型
作者
Rédouane Aherrahrou,Ferheen Baig,Konstantinos Theofilatos,Dillon Lue,Alicia Beele,Tiit Örd,Minna U. Kaikkonen,Zouhair Aherrahrou,Qi Cheng,Saikat Ghosh,Santosh Karnewar,Vaishnavi Karnewar,Aloke V. Finn,Gary K. Owens,Michael Joner,Manuel Mayr,Mete Civelek
标识
DOI:10.1161/atvbaha.123.320274
摘要
BACKGROUND: Smooth muscle cells (SMCs), which make up the medial layer of arteries, are key cell types involved in cardiovascular disease, the leading cause of mortality and morbidity worldwide. In response to microenvironment alterations, SMCs dedifferentiate from a contractile to a synthetic phenotype characterized by an increased proliferation, migration, production of ECM (extracellular matrix) components, and decreased expression of SMC-specific contractile markers. These phenotypic changes result in vascular remodeling and contribute to the pathogenesis of cardiovascular disease, including coronary artery disease, stroke, hypertension, and aortic aneurysms. Here, we aim to identify the genetic variants that regulate ECM secretion in SMCs and predict the causal proteins associated with vascular disease–related loci identified in genome-wide association studies. METHODS: Using human aortic SMCs from 123 multiancestry healthy heart transplant donors, we collected the serum-free media in which the cells were cultured for 24 hours and conducted liquid chromatography–tandem mass spectrometry-based proteomic analysis of the conditioned media. RESULTS: We measured the abundance of 270 ECM and related proteins. Next, we performed protein quantitative trait locus mapping and identified 20 loci associated with secreted protein abundance in SMCs. We functionally annotated these loci using a colocalization approach. This approach prioritized the genetic variant rs6739323-A at the 2p22.3 locus, which is associated with lower expression of LTBP1 (latent-transforming growth factor beta-binding protein 1) in SMCs and atherosclerosis-prone areas of the aorta, and increased risk for SMC calcification. We found that LTBP1 expression is abundant in SMCs, and its expression at mRNA and protein levels was reduced in unstable and advanced atherosclerotic plaque lesions. CONCLUSIONS: Our results unravel the SMC proteome signature associated with vascular disorders, which may help identify potential therapeutic targets to accelerate the pathway to translation.
科研通智能强力驱动
Strongly Powered by AbleSci AI