2. Academic Validation
  3. CircNAP1L4 regulates pulmonary artery smooth muscle cell proliferation via the NAP1L4-mediated super-enhancer-driven glycolysis gene hexokinase II (HK II) in pulmonary hypertension

CircNAP1L4 regulates pulmonary artery smooth muscle cell proliferation via the NAP1L4-mediated super-enhancer-driven glycolysis gene hexokinase II (HK II) in pulmonary hypertension

  • FASEB J. 2024 Aug 15;38(15):e23868. doi: 10.1096/fj.202400585RRR.
Xiaoying Wang 1 2,  Xiaoyu Guan 1 3,  Xiangrui Zhu 4,  Lixin Zhang 1 4,  Cui Ma 1 4,  Siyu He 5,  June Bai 1 3,  Jian Mei 4,  Qian Li 3,  Na Sun 6 7,  Bingxiang Wu 6 7,  Daling Zhu 1 3 8
Affiliations

Affiliations

  • 1 Central Laboratory of Harbin Medical University (Daqing), Daqing, P. R. China.
  • 2 College of Pharmacy, Harbin Medical University (Daqing), Daqing, P. R. China.
  • 3 College of Pharmacy, Harbin Medical University, Harbin, P. R. China.
  • 4 College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), Daqing, P. R. China.
  • 5 Shenzhen Key Laboratory of Respiratory Disease, Shenzhen People's Hospital, Shenzhen, P. R. China.
  • 6 Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, P. R. China.
  • 7 Key Laboratory of Myocardial Ischemia, Ministry Education, Harbin Medical University, Harbin, P. R. China.
  • 8 Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Harbin Medical University, Harbin, P. R. China.
PMID: 39102213 DOI: 10.1096/fj.202400585RRR
Abstract

Glycolysis is a major determinant of pulmonary artery smooth muscle cell (PASMC) proliferation in pulmonary hypertension (PH). Circular RNAs (circRNAs) are powerful regulators of glycolysis in multiple diseases; however, the role of circRNAs in glycolysis in PH has been poorly characterized. The aim of this study was to uncover the regulatory mechanism of a new circRNA, circNAP1L4, in human pulmonary artery smooth muscle cell (HPASMC) proliferation through the host protein NAP1L4 to regulate the super-enhancer-driven glycolysis gene Hexokinase II (HK II). CircNAP1L4 was downregulated in hypoxic HPASMCs and plasma of PH patients. Functionally, circNAP1L4 overexpression inhibited glycolysis and proliferation in hypoxic HPASMCs. Mechanistically, circNAP1L4 directly bound to its host protein NAP1L4 and affected the ability of NAP1L4 to move into the nucleus to regulate the epigenomic signals of the super-enhancer of HK II. Intriguingly, circNAP1L4 overexpression inhibited the proliferation but not the migration of human pulmonary arterial endothelial cells (HPAECs) cocultured with HPASMCs. Furthermore, pre-mRNA-processing-splicing Factor 8 (PRP8) was found to regulate the production ratio of circNAP1L4 and linear NAP1L4. In vivo, targeting circNAP1L4 alleviates SU5416 combined with hypoxia (SuHx)-induced PH. Overall, these findings reveal a new circRNA that inhibits PASMC proliferation and serves as a therapeutic target for PH.

Keywords

CircNAP1L4; glycolysis; proliferation; pulmonary hypertension; super‐enhancer.

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