Abstract Body: Background: Ionizing radiation (IR) is a well-recognized contributor to cardiovascular disease, in part through endothelial cell (EC) injury characterized by oxidative stress, DNA damage, telomere dysfunction, and premature cellular senescence. These processes drive chronic inflammation and accelerate atherosclerosis (AthS). Although the serine/threonine kinase p90RSK regulates multiple stress-responsive and inflammatory pathways, its role in IR-induced chromosomal instability and long-term vascular injury remains incompletely understood.

Hypothesis: Pharmacologic Inhibition of p90RSK following irradiation mitigates IR-induced DNA damage and ECs senescence by restoring chromosomal and telomere stability, thereby attenuating IR-accelerated AthS.

Methods: Human Umbilical Vein Endothelial Cells were exposed to 5 Gy X-radiation and treated with p90RSK inhibitors (FMK-MEA or BI-D1870). Genomic instability and DNA damage were assessed using dicentric chromosome assays, micronucleus analysis, chromosome orientation–fluorescence in situ hybridization, and neutral comet assays. Transcriptomic changes were evaluated by RNA sequencing. In vivo relevance was examined using a partial carotid ligation model of radiation-accelerated AthS.

Results: IR induced marked increases in chromosomal aberrations, telomere instability, and DNA double-strand breaks in ECs, accompanied by sustained activation of senescence-associated and pro-inflammatory transcriptional programs. Post-IR inhibition of p90RSK significantly reduced both acute and persistent genomic damage, restored telomere stability, and suppressed EC senescence and senescence associated secretory phenotype. In vivo, p90RSK inhibition attenuated IR-mediated acceleration of AthS. Transcriptomic analyses identified KCNK6, a potassium channel linked to inflammatory signaling, as a novel and downstream effector uniquely reversed by p90RSK inhibition. Genetic depletion of KCNK6 recapitulated the protective effects of p90RSK inhibition, reducing IR-induced senescence and inflammatory signaling.
Conclusion: p90RSK serves as a central mediator of IR-induced endothelial genomic instability, linking DNA damage to cellular senescence and AthS progression. Pharmacologic inhibition of p90RSK provides durable vascular radioprotection by preserving chromosomal and telomere integrity and suppressing inflammatory remodeling, identifying p90RSK and KCNK6 as therapeutic targets for radiation-associated cardiovascular disease.