ADAR1 regulates vascular remodeling in hypoxic pulmonary hypertension through N1-methyladenosine modification of circCDK17

Zhang，Junting1; Li，Yiying1; Zhang，Jianchao1; Liu，Lu2; Chen，Yuan3; Yang，Xusheng3; Liao，Xueyi1; He，Muhua2; Jia，Zihui3; Fan，Jun4; Bian，Jin Song2; Nie，Xiaowei1

2023

10.1016/j.apsb.2023.07.006

Acta Pharmaceutica Sinica B   Impact Factor & Quartile

2211-3835

2211-3843

Pulmonary hypertension (PH) is an extremely malignant pulmonary vascular disease of unknown etiology. ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine, thereby affecting RNA expression. However, the role of ADAR1 in PH development remains unclear. In the present study, we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling. Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells (PASMCs). Conversely, inhibition of ADAR1 produced opposite effects. High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH. CircCDK17 level was significantly lowered in the serum of PH patients. The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17. ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from m1A modification. We demonstrate for the first time that ADAR1 contributes to the PH development, at least partially, through m1A modification of circCDK17 and the subsequent PASMCs proliferation. Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.

ADAR1 Cell proliferation Circular RNA Pulmonary hypertension Vascular remodeling

English

First

2-s2.0-85165937546

Scopus

1.Shenzhen Institute of Respiratory Disease,Shenzhen Key Laboratory of Respiratory Disease,Shenzhen People's Hospital (the Second Clinical Medical College,Jinan University;,the First Affiliated Hospital,Southern University of Science and Technology),Post-Doctoral Scientific Research Station of Basic Medicine,Jinan University,Guangzhou,Shenzhen 518020, China;,510632,China
2.Department of Pharmacology,School of Medicine,Southern University of Science and Technology,Shenzhen,518055,China
3.Lung Transplant Group,Wuxi People's Hospital Affiliated to Nanjing Medical University,Wuxi,211103,China
4.Department of Medical Biochemistry and Molecular Biology,School of Medicine,Jinan University,Guangzhou,510632,China

Zhang，Junting,Li，Yiying,Zhang，Jianchao,et al. ADAR1 regulates vascular remodeling in hypoxic pulmonary hypertension through N1-methyladenosine modification of circCDK17[J]. Acta Pharmaceutica Sinica B,2023.

Zhang，Junting.,Li，Yiying.,Zhang，Jianchao.,Liu，Lu.,Chen，Yuan.,...&Nie，Xiaowei.(2023).ADAR1 regulates vascular remodeling in hypoxic pulmonary hypertension through N1-methyladenosine modification of circCDK17.Acta Pharmaceutica Sinica B.

Zhang，Junting,et al."ADAR1 regulates vascular remodeling in hypoxic pulmonary hypertension through N1-methyladenosine modification of circCDK17".Acta Pharmaceutica Sinica B (2023).