Accelerated RNA polymerase II elongation drives endothelial transition and plaque vulnerability: pharmacological targeting of the super elongation complex [RNA-seq]

Atherosclerotic plaque rupture is a major cause of myocardial infarction and stroke, yet the mechanisms governing plaque stability remain incompletely understood. Endothelial activation can trigger endothelial-to-mesenchymal transition, a program linked to endothelial dysfunction and lesion vulnerability. Here we investigated whether transcriptional pause release and RNA polymerase II elongation constitute an early regulatory layer that promotes endothelial-to-mesenchymal transition and atherosclerosis. Analysis of human plaque single-nucleus transcriptomics indicated increased expression of super elongation complex components in endothelial cells with a transition signature. In primary human endothelial cell models, pharmacological inhibition of the super elongation complex attenuated induction of mesenchymal markers. AFF4, pCDK9, and pSMAD2/3, showed physical interaction during endothelial transition. Genome-wide profiling of RNA polymerase II occupancy revealed reduced promoter-proximal pausing during early transition, accompanied by a rapid increase in nascent transcriptional elongation rates. Super elongation complex inhibition restored pausing and suppressed fast-responding transition-associated target genes. In a human cardiac organoid model, inhibition of the super elongation complex prevented EndMT-induced fibrillar collagen deposition and reduction in cardiomyocyte beating rate. In a hyperlipidemic Pcsk9 gain-of-function mouse model, super elongation complex inhibition administered both prophylactically and therapeutically after established atherosclerosis reduced plaque burden and improved features associated with vulnerability. Finally, analysis of 1,048 human plaque segments from the Athero-Express biobank showed significant associations between the elongation axis and multiple vulnerability-related plaque traits. Together, these findings identify rapid transcriptional elongation as a mechanistic driver of endothelial plasticity and features of plaque vulnerability and support targeting the elongation machinery as a potential strategy to stabilize atherosclerotic disease.