Inflammatory and Structural Endotypes of Human Atherosclerotic Plaque Revealed by Integrated Transcriptomic Analysis

Area of Science:

• Cardiovascular Biology
• Transcriptomics
• Atherosclerosis Research

Background:

• Atherosclerotic plaque instability arises from complex inflammatory, structural, and cellular remodeling processes.
• Bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) offer complementary views of tissue and cellular transcriptional states, but their integration is limited.
• Understanding coordinated transcriptional programs is crucial for differentiating stable from unstable plaque phenotypes.

Purpose of the Study:

• To identify coordinated transcriptional programs associated with stable and unstable atherosclerotic plaque phenotypes.
• To map these programs to specific cellular compartments and regulatory networks.
• To integrate bulk and single-cell transcriptomic data for a comprehensive understanding of plaque biology.

Main Methods:

• Analysis of paired bulk RNA-seq data from human carotid plaques and scRNA-seq data from coronary lesions.
• Differential expression and gene set enrichment analyses using limma and clusterProfiler.
• Projection of bulk-derived signatures onto single-cell data, compartment-level scoring, and transcription factor activity inference.

Main Results:

• Unstable plaques showed enrichment of inflammatory pathways (e.g., interferon gamma, TNFα/NF-κB, IL6/JAK/STAT3).
• Stable plaques exhibited enrichment of myogenesis and structural remodeling programs.
• Inflammatory programs localized to macrophages, while structural programs mapped to smooth muscle cells; distinct transcription factor activities were identified in stable vs. unstable plaques.

Conclusions:

• Integrative transcriptomic analysis revealed distinct inflammatory and structural states linked to plaque stability.
• Findings support a systems-level framework connecting tissue-level plaque behavior to cellular and regulatory programs.
• Evidence for inflammatory and structural plaque endotypes in human atherosclerosis was provided.