8OH-G miR-483 contributes to the aging-accelerated atherosclerosis

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Project Summary/Abstract Atherosclerosis is a sequela of aging, in part, because aging exacerbates the atherogenic factors (e.g., oxidative stress), which induces endothelial cells (ECs) senescence. MicroRNAs (miRs) are ubiquitously involved in epigenetic regulation of gene expression by targeting the 3’-untranslated region (3’UTR) of the protein-encoded transcripts. Recently, we have reported that the miR-483 endows anti-endoMT, anti-fibrotic, and anti- inflammatory effects on the endothelium, contributing to a homeostatic endothelium. Emerging evidence indicates that oxidative stress can cause hydroxylation of guanine (G) in miRs to generate 8-oxo-7,8-dihydro guanosine (8OH-G) which induces the guanine-to-uracil (G-U) transversion of miRs. Because 8OH-G pairs with adenine (A), the oxidative stress-modified miRs no longer target their authentic mRNA effectually. This epitranscriptomic change results in distinctive functions in the cell, therefore sways the disease process. In the newly conducted pilot studies, we found elevated levels of 8OH-G miR-483 in senescent ECs in culture and vascular intima in aging mice. Moreover, EC function is affected by the molar ratio of miR-483/8OH-G miR-483, revealed by RNA-seq. These newly acquired results lead to the overarching hypothesis that the aging-induced miR-483 to 8OH-G miR-483 transversion causes EC senescence and dysfunction. Mechanistically, this miR epitranscriptomic change alters mRNA targetomes in ECs, which instigates aging-induced EC dysfunction and thereby aggravating atherosclerosis. To test this hypothesis, the following two specific aims are proposed: Aim 1. To delineate the molecular mechanism by which aging-induced 8OH-G miR-483 impairs EC function. Specifically, we will decipher the 8OH-G miR-483 epitranscriptomes by investigating the aging-associated G-to- U transversion of miR-483 and the specificity of 8OH-G-miR-483 targeting mRNAs. We will also study the sequelae of 8OH-G miR-483 with respect to EC senescence. Aim 2. To investigate the atheroprone effect of 8OH-G miR-483 in aging mice. We will introduce atherosclerosis in young and aged iEC-miR-483-Tg and their wildtype littermate mice. Atherosclerosis and vascular functions will be compared among young and old mice as functions of G-to-8OH-G miR-483 ratio and deduced 8OH-G miR-483 regulatory network. With the use of in vitro and in vivo experimental models, this exploratory research proposal will decipher the role of miR-483 to 8OH-G miR-483 transversion in EC biology and aging-deteriorated atherosclerosis.