Abstract P2156: Endothelium-targeting Exosomes Ameliorate Cardiac Senescence Via Delivery Of Line1 Antisense Oligonucleotides In A Mouse Model Of Myocardial Infarction

Abstract

Transposable elements (TEs), which include long-interspersed element-1 (LINE1) retrotransposon, highly constitute the genome of mammals and their dysregulation is considered the stimulatory factor of genomic damage and innate interferon response and unnatural senescence. The objectives of this study are to determine the functions of LINE1 retrotransposon during myocardial infarction (MI). In this study, selectins, CD62E and CD62P, are identified as the biomarker of the injured endothelial cells in MI. Furthermore, selectin binding peptide (SBP)-engineered extracellular vesicles (SBP-EVs) with targeting functions are developed. We further investigated the SBP-EVs with therapeutic effects by packing LINE1 antisense oligonucleotides (SBP-LINE1-EVs). The results show that SBP-LINE1-EVs exhibit a selective targeting tendency to injured heart with an enhanced myocardium protection effect by LINE1 antisense oligonucleotides delivery. SBP-LINE1-EVs protected against myocardial senescence by inhibiting the reactivation of the innate immune cGAS-STING-TBK1-IRF3 pathway and further repressing the expressions of senescence-associated secretory phenotype (SASP) factors. In conclusion, our findings establish the causal relationship among LINE1, cardiac senescence, and myocardial infarction for the first time. Moreover, we demonstrate the enhanced therapeutic efficacy of the bifunctional SBP-LINE1-EVs system and provide preclinical evidence for targeted therapy of MI by LINE1 inhibition in future clinical applications.