Analysis of Combined Transcriptomes Identifies Gene Modules that Differentially Respond to Pathogenic Stimulation of...

Area of Science:

• Vascular Biology
• Transcriptomics
• Cardiovascular Research

Background:

• Smooth muscle cells (SMCs) and endothelial cells (ECs) are critical for vascular health, forming the medial wall and inner lining, respectively.
• Current cardiovascular disease treatments targeting SMC hyperplasia can damage ECs, increasing thrombosis risk.
• Understanding differential gene regulation in SMCs versus ECs is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the differential transcriptomic responses of human primary SMCs and ECs to inflammatory stimuli (TNFα and IL-1β).
• To identify specific gene sets and regulatory modules enriched in SMCs or ECs following cytokine treatment.
• To uncover potential therapeutic targets for selective inhibition of SMC hyperplasia with minimal EC damage.

Main Methods:

• RNA sequencing (RNA-seq) was performed on human primary SMCs and ECs treated with TNFα or IL-1β.
• Differential gene expression analysis was conducted to identify SMC-enriched and EC-enriched genes.
• Gene interaction network analysis was used to identify central genes and gene modules within the enriched sets.

Main Results:

• TNFα and IL-1β induced distinct transcriptomic changes in SMCs and ECs.
• 174-213 genes were SMC-enriched, and 117-138 genes were EC-enriched after stimulation.
• Four key gene modules were identified: JUN and FYN (SMC-enriched), and SMAD3 and XPO1 (EC-enriched).

Conclusions:

• Differential gene regulation in SMCs and ECs under inflammatory conditions has been characterized.
• Identified SMC- and EC-enriched gene modules, including JUN, FYN, SMAD3, and XPO1, represent potential therapeutic targets.
• These findings pave the way for developing selective SMC hyperplasia inhibitors that preserve EC function and reduce thrombosis risk.