Superenhancer-driven circRNA Myst4 involves in pulmonary artery smooth muscle cell ferroptosis in pulmonary hypertension
Siyu He,
June Bai,
Lixin Zhang,
Hao Yuan,
Cui Ma,
Xiaoying Wang,
Xiaoyu Guan,
Jian Mei,
Xiangrui Zhu,
Wei Xin,
Daling Zhu
Affiliations
Siyu He
Central Laboratory of Harbin Medical University (Daqing), Daqing 163319, P.R. China; College of Pharmacy, Harbin Medical University, Harbin 150081, P.R. China
June Bai
Central Laboratory of Harbin Medical University (Daqing), Daqing 163319, P.R. China; College of Pharmacy, Harbin Medical University, Harbin 150081, P.R. China
Lixin Zhang
Central Laboratory of Harbin Medical University (Daqing), Daqing 163319, P.R. China; College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), Daqing 163319, P.R. China
Hao Yuan
Central Laboratory of Harbin Medical University (Daqing), Daqing 163319, P.R. China; College of Pharmacy, Harbin Medical University, Harbin 150081, P.R. China
Cui Ma
Central Laboratory of Harbin Medical University (Daqing), Daqing 163319, P.R. China; College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), Daqing 163319, P.R. China
Xiaoying Wang
Central Laboratory of Harbin Medical University (Daqing), Daqing 163319, P.R. China; College of Pharmacy, Harbin Medical University (Daqing), Daqing 163319, P.R. China
Xiaoyu Guan
Central Laboratory of Harbin Medical University (Daqing), Daqing 163319, P.R. China; College of Pharmacy, Harbin Medical University, Harbin 150081, P.R. China
Jian Mei
College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), Daqing 163319, P.R. China
Xiangrui Zhu
College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), Daqing 163319, P.R. China
Wei Xin
Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200031, P.R. China
Daling Zhu
Central Laboratory of Harbin Medical University (Daqing), Daqing 163319, P.R. China; College of Pharmacy, Harbin Medical University, Harbin 150081, P.R. China; Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Harbin Medical University, Harbin 150081, P.R. China; Corresponding author
Summary: The abnormal expression of circular RNAs (circRNAs) is emerging as a critical cause in regulation of pathological changes of hypoxic pulmonary hypertension (PH), in which ferroptosis is a new pathological change reported recently. However, how circRNAs regulate ferroptosis remains unclear. Here, we proved a significant decrease in circMyst4 expression in hypoxia. In vitro assays revealed that circMyst4 alleviated hypoxic pulmonary artery smooth muscle cell (PASMC) ferroptosis through directly combing with DDX5 in the nucleus to promote GPX4 mRNA processing and inhibiting the formation of the Eef1a1/ACSL4 complex in the cytoplasm. Additionally, superenhancer (SE) was verified to drive the generation of circMyst4. In vivo assays revealed that circMyst4 inhibited the progression of hypoxic PH. Overall, SE-driven circMyst4 may be a new potential therapeutic target for mediating PASMC ferroptosis through promoting DDX5-regulated GPX4 mRNA processing and inhibiting the binding between Eef1a1 and ACSL4.
