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

doi:10.1038/s41467-022-34433-z

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

Life Sciences

Research output: Contribution to journal › Article › peer-review

6 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 language	English
Article number	6647
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34433-z
State	Published - Dec 2022

Bibliographical note

Funding Information:
The apparatus including LSM 780 NLO (Zeiss), LSRFortessa (Becton Dickinson), and FACSAria (Becton Dickinson) at Ewha Fluorescence Core Imaging Center were utilized for major experiments. We acknowledge Hyun Jung Park for designing the graphical illustration used in this study. The GTEx data were obtained from: the GTEx portal/dbGaP accession number phs000424.v8.p2 on 09/06/2022. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2020R1A3B2079811; G.T.O. and NRF-2021M3E5E7023628; G.T.O.).

Funding Information:
The apparatus including LSM 780 NLO (Zeiss), LSRFortessa (Becton Dickinson), and FACSAria (Becton Dickinson) at Ewha Fluorescence Core Imaging Center were utilized for major experiments. We acknowledge Hyun Jung Park for designing the graphical illustration used in this study. The GTEx data were obtained from: the GTEx portal/dbGaP accession number phs000424.v8.p2 on 09/06/2022. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2020R1A3B2079811; G.T.O. and NRF-2021M3E5E7023628; G.T.O.).

Publisher Copyright:
© 2022, The Author(s).

Access to Document

10.1038/s41467-022-34433-z

Cite this

Kim, T. K., Jeon, S., Park, S., Sonn, S. K., Seo, S., Suh, J., Jin, J., Kweon, H. Y., Kim, S., Moon, S. H., Kweon, O., Koo, B. H., Kim, N., Lee, H. O., Kim, Y. M., Kim, Y. J., Park, S. H., & Oh, G. T. (2022). 2′–5′ oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability. Nature Communications, 13(1), Article 6647. https://doi.org/10.1038/s41467-022-34433-z

@article{e7bc067f262a419e95d24aa82dd0d641,

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

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.",

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

note = "Funding Information: The apparatus including LSM 780 NLO (Zeiss), LSRFortessa (Becton Dickinson), and FACSAria (Becton Dickinson) at Ewha Fluorescence Core Imaging Center were utilized for major experiments. We acknowledge Hyun Jung Park for designing the graphical illustration used in this study. The GTEx data were obtained from: the GTEx portal/dbGaP accession number phs000424.v8.p2 on 09/06/2022. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2020R1A3B2079811; G.T.O. and NRF-2021M3E5E7023628; G.T.O.). Funding Information: The apparatus including LSM 780 NLO (Zeiss), LSRFortessa (Becton Dickinson), and FACSAria (Becton Dickinson) at Ewha Fluorescence Core Imaging Center were utilized for major experiments. We acknowledge Hyun Jung Park for designing the graphical illustration used in this study. The GTEx data were obtained from: the GTEx portal/dbGaP accession number phs000424.v8.p2 on 09/06/2022. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2020R1A3B2079811; G.T.O. and NRF-2021M3E5E7023628; G.T.O.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-34433-z",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Kim, TK, Jeon, S, Park, S, Sonn, SK, Seo, S, Suh, J, Jin, J, Kweon, HY, Kim, S, Moon, SH, Kweon, O, Koo, BH, Kim, N, Lee, HO, Kim, YM, Kim, YJ, Park, SH & Oh, GT 2022, '2′–5′ oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability', Nature Communications, vol. 13, no. 1, 6647. https://doi.org/10.1038/s41467-022-34433-z

TY - JOUR

T1 - 2′–5′ oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability

AU - Kim, Tae Kyeong

AU - Jeon, Sejin

AU - Park, Seonjun

AU - Sonn, Seong Keun

AU - Seo, Seungwoon

AU - Suh, Joowon

AU - Jin, Jing

AU - Kweon, Hyae Yon

AU - Kim, Sinai

AU - Moon, Shin Hye

AU - Kweon, Okhee

AU - Koo, Bon Hyeock

AU - Kim, Nayoung

AU - Lee, Hae Ock

AU - Kim, Young Myeong

AU - Kim, Young Joon

AU - Park, Sung Ho

AU - Oh, Goo Taeg

N1 - Funding Information: The apparatus including LSM 780 NLO (Zeiss), LSRFortessa (Becton Dickinson), and FACSAria (Becton Dickinson) at Ewha Fluorescence Core Imaging Center were utilized for major experiments. We acknowledge Hyun Jung Park for designing the graphical illustration used in this study. The GTEx data were obtained from: the GTEx portal/dbGaP accession number phs000424.v8.p2 on 09/06/2022. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2020R1A3B2079811; G.T.O. and NRF-2021M3E5E7023628; G.T.O.). Funding Information: The apparatus including LSM 780 NLO (Zeiss), LSRFortessa (Becton Dickinson), and FACSAria (Becton Dickinson) at Ewha Fluorescence Core Imaging Center were utilized for major experiments. We acknowledge Hyun Jung Park for designing the graphical illustration used in this study. The GTEx data were obtained from: the GTEx portal/dbGaP accession number phs000424.v8.p2 on 09/06/2022. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2020R1A3B2079811; G.T.O. and NRF-2021M3E5E7023628; G.T.O.). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85141191733&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-34433-z

DO - 10.1038/s41467-022-34433-z

M3 - Article

C2 - 36333342

AN - SCOPUS:85141191733

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6647

ER -

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

Abstract

Bibliographical note

Access to Document

Fingerprint

Cite this