横截
小RNA
鸟嘌呤
生物
基因敲除
内皮功能障碍
鸟苷
分子生物学
转录组
内科学
内分泌学
化学
生物化学
基因
基因表达
核苷酸
医学
突变
作者
Ming He,Jianjie Dong,Yuqing Zhang,So Yun Han,Chen Wang,Brendan Gongol,Jian Kang,Hsi‐Yuan Huang,John Y.‐J. Shyy
标识
DOI:10.1101/2022.05.21.492858
摘要
Abstract Emerging evidence indicates that oxidative stress causes the hydroxylation of guanine (G) to generate 8-oxo-7,8-dihydro guanosine ( 8 OH-G) in microRNAs (miRs), which induces the guanine-to-uracil (G-to-U) transversion and thus changes the miR targetomes. However, whether and how the 8 OH-G-modified miRs are involved in vascular endothelial dysfunction and atherogenesis were unexplored. Using 8 OH-G crosslinking immunoprecipitation miR sequencing (8OH-G CLIP-miR-seq), we found that 8 OH-G miR-483 were among the most enriched 8 OH-G miR species in ECs induced by ox-LDL. Transcriptomic profiling by RNA-seq indicated that the G-to-U transversion of miR-483 altered the original mRNA targeting efficacy and allows 8 OH-G miR-483 to recognize new mRNA target sites. A reduced ratio of 8 OH-G miR-483 to miR-483 in lung ECs was found in the endothelial-specific miR-483 transgenic (EC-miR-483 Tg) mice. Moreover, reduction of atherosclerosis was significant in EC-miR-483 Tg mice administrated AAV8-PCSK9 and fed an atherogenic diet. In situ miR hybridization revealed an increased 8 OH-G miR-483 level in the intima of human atherosclerotic arteries. Collectively, this study demonstrates that the redox burden incurred by cardiovascular risk factors is a culprit of the miR-483 to 8 OH-G miR-483 transversion. Such epitranscriptomic modification of miR-483 causes endothelial dysfunction and increases atherosclerosis susceptibility via its targetomes shift.
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