Transcriptional Pause Release and RNA Polymerase II Elongation Drive Atherosclerotic Plaque Instability

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Summary of  Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-026-02962-4 
Dr. Karoline E. Kokot et al.

Points

Researchers at Leipzig University Medical Center discovered that the speed of RNA polymerase II elongation by the super elongation complex drives endothelial transformation and atherosclerotic plaque vulnerability.
Pharmacological inhibition of the super elongation complex restored promoter-proximal pausing, suppressed mesenchymal transition markers, and maintained vascular barrier integrity in human primary endothelial cell models.
Experiments utilizing human cardiac organoid tissue demonstrated that inhibiting transcriptional elongation prevented excessive fibrillar collagen deposition and preserved normal heart muscle beating rate kinetics.
In hyperlipidemic mouse models with established atherosclerosis, super elongation complex inhibition reduced overall plaque burden, decreased macrophage infiltration, and attenuated key features of lesion instability.
Analysis of over one thousand human plaque segments from the Athero-Express biobank confirmed a direct link between elevated elongation machinery expression and clinical markers of plaque vulnerability.

Summary

This study evaluated the regulatory role of transcriptional pause release and rapid RNA polymerase II elongation in driving endothelial-to-mesenchymal transition (EndMT) and atherosclerotic plaque vulnerability. Published in Signal Transduction and Targeted Therapy by researchers at Leipzig University Medical Center, the investigation examined how the super elongation complex (SEC)—comprising AFF4, pCDK9, and pSMAD2/3 physical interactions—promotes pathological endothelial plasticity under inflammatory and altered shear stress conditions. The study sought to determine whether targeting transcriptional elongation machinery could preserve vascular barrier integrity and stabilize vulnerable lesions.

Genome-wide profiling of RNA polymerase II occupancy revealed reduced promoter-proximal pausing during early EndMT, causing accelerated nascent transcriptional elongation rates. Pharmacological inhibition of the SEC restored promoter pausing and suppressed fast-responding transition target genes. In human cardiac organoid models, SEC inhibition attenuated EndMT-induced fibrillar collagen deposition and preserved beating rate kinetics. In hyperlipidemic Pcsk9 gain-of-function mouse models, SEC inhibition administered both prophylactically and therapeutically significantly reduced total plaque burden, macrophage infiltration, and features of lesion vulnerability.

Translational relevance was validated using single-cell transcriptomics and histological analysis of 1,048 human plaque segments from the Athero-Express biobank at Utrecht University. The analysis confirmed significant associations between expression of the elongation axis and specific vulnerability-related plaque traits in patient tissue. The authors conclude that transcriptional elongation kinetics serve as a key driver of endothelial dysfunction, supporting SEC and CDK9 inhibition as potential therapeutic strategies to prevent plaque rupture, myocardial infarction, and stroke.

Link to the article: https://www.nature.com/articles/s41392-026-02962-4

References

Kokot, K. E., Reichardt, S., Menedo, C., Erbe, S., Kneuer, J. M., Palm, K. C. A., Hoba, J., Andritschke, M., Katzmann, M., Reuser, A., von Scheidt, M., Mokry, M., Xiao, J., Sheikh, B. N., Klöting, N., Laufs, U., & Boeckel, J.-N. (2026). Targeting super elongation complex-driven RNA polymerase II elongation reduces plaque vulnerability. Signal Transduction and Targeted Therapy, 11(1), 385. https://doi.org/10.1038/s41392-026-02962-4