Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Genomics

Background:

• Atherosclerosis progression involves complex changes in vascular cell gene expression.
• The clinical relevance of these single-cell gene expression changes is not well understood.

Purpose of the Study:

• To investigate the clinical and pathophysiological relevance of single-cell gene expression patterns in atherosclerosis.
• To identify key gene regulatory networks (GRNs) associated with advanced and symptomatic atherosclerosis.

Main Methods:

• Single-cell RNA sequencing of 16,588 cells from mouse models and human carotid plaques.
• Integration of single-cell data with 135 tissue-specific GRNs from the STARNET study.
• Validation of identified GRNs and key drivers in independent datasets and cell culture.

Main Results:

• Three smooth muscle cell (SMC) and three macrophage subtypes characterized advanced atherosclerosis.
• Integrative analysis revealed significant enrichment of GRN33, GRN39, and GRN122 with coronary artery disease (CAD) heritability.
• GRN39, associated with SMCs, was strongly linked to coronary atherosclerosis severity and validated in independent human datasets.

Conclusions:

• GRN39 is identified as a critical gene regulatory network in atherosclerosis.
• GRN39 drives the transformation of contractile SMCs to an osteogenic phenotype.
• This transformation promotes advanced, symptomatic atherosclerosis, highlighting GRN39's pathophysiological relevance.