2′–5′ oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability

Tae Kyeong Kim, Sejin Jeon, Seonjun Park, Seong Keun Sonn, Seungwoon Seo, Joowon Suh, Jing Jin, Hyae Yon Kweon, Sinai Kim, Shin Hye Moon, Okhee Kweon, Bon Hyeock Koo, Nayoung Kim, Hae Ock Lee, Young Myeong Kim, Young Joon Kim, Sung Ho Park, Goo Taeg Oh

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10 Scopus citations

Abstract

Endothelial nitric oxide synthase (eNOS) decreases following inflammatory stimulation. As a master regulator of endothelial homeostasis, maintaining optimal eNOS levels is important during cardiovascular events. However, little is known regarding the mechanism of eNOS protection. In this study, we demonstrate a regulatory role for endothelial expression of 2′–5′ oligoadenylate synthetase-like 1 (OASL1) in maintaining eNOS mRNA stability during athero-prone conditions and consider its clinical implications. A lack of endothelial Oasl1 accelerated plaque progression, which was preceded by endothelial dysfunction, elevated vascular inflammation, and decreased NO bioavailability following impaired eNOS expression. Mechanistically, knockdown of PI3K/Akt signaling-dependent OASL expression increased Erk1/2 and NF-κB activation and decreased NOS3 (gene name for eNOS) mRNA expression through upregulation of the negative regulatory, miR-584, whereas a miR-584 inhibitor rescued the effects of OASL knockdown. These results suggest that OASL1/OASL regulates endothelial biology by protecting NOS3 mRNA and targeting miR-584 represents a rational therapeutic strategy for eNOS maintenance in vascular disease.

Original languageEnglish
Article number6647
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

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