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

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.