AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Post-Exposure p90RSK Inhibition Attenuates Radiation-Induced Endothelial Genomic Instability and Atherosclerosis Through KCNK6 and PIDD1 Signaling
By Chu KY, Rivera L, Li Q et al.
Background: Post-radiation cardiovascular disease (CVD) is a major long-term consequence of ionizing radiation (IR), driven largely by endothelial cell (EC) dysfunction. IR induces oxidative stress, DNA damage, senescence, and vascular inflammation, accelerating atherosclerosis. The kinase p90RSK regulates several of these processes, but its role in IR-induced genomic instability remains incompletely defined. This study investigated whether p90RSK contributes to IR-induced genomic damage in ECs and whether post-exposure inhibition can mitigate telomere dysfunction and cytogenetic abnormalities. Methods: IR-induced atherosclerosis was evaluated using the partial carotid ligation model. ECs were exposed to 5 Gy X-radiation followed by treatment with p90RSK inhibitors FMK-MEA or BI-D1870. Genomic instability was assessed using dicentric chromosome and micronucleus assays, telomere integrity by CO-FISH, and DNA double-strand breaks by neutral Comet assay. RNA sequencing identified downstream targets, including KCNK6 (potassium two-pore domain channel subfamily K member 6, a regulator of membrane potential and cellular stress responses) and PIDD1 (p53-induced death domain protein 1, a mediator of DNA damage-induced apoptosis and cell-cycle control). Gain- and loss-of-function studies examined their roles in IR-induced endothelial responses. Results: Both FMK-MEA and BI-D1870 significantly reduced IR-induced atherosclerotic lesion formation, even when administered after radiation exposure. IR increased genomic instability, including dicentric chromosomes, micronuclei, telomere sister chromatid exchanges, and DNA breaks; these were attenuated by both inhibitors, with FMK-MEA showing stronger effects on telomeric damage. RNA sequencing identified KCNK6 as a shared downstream target of both inhibitors, implicating it in p90RSK-mediated telomere dysfunction, endothelial senescence, and vascular injury. In contrast, PIDD1 was enriched in BI-D1870-regulated pathways, including p53 signaling, apoptosis, DNA damage response, and inflammation. Functional studies showed that both KCNK6 and PIDD1 regulate IR-induced senescence and apoptosis, while PIDD1 depletion reduced cell-cycle arrest. Notably, BI-D1870 suppressed PIDD1 independently of p90RSK. Conclusions: p90RSK is a central mediator of IR-induced endothelial dysfunction through KCNK6-dependent genomic instability and telomere damage. PIDD1 represents a parallel regulator of DNA damage responses, partially independent of p90RSK. Pharmacological inhibition of p90RSK mitigates cytogenetic damage and vascular injury even after IR exposure, supporting the p90RSK-KCNK6 axis as a promising therapeutic target for radiation-induced CVD.