3 ' UTR shortening of HAS2 promotes hyaluronan hyper-synthesis and bioenergetic dysfunction in pulmonary hypertension

• Type of Material: Article
• Authors: Victor Tseng, Ansible Health Mountain View, CA; Scott D Collum, University of Texas, Houston; Ayed Allawzi, Translate Bio, Lexington; Kathryn Crotty, Emory University; Samantha Yeligar, Emory University; Aaron Trammell, Emory University; M. Ryan Smith, Emory University; Bum-Yong Kang, Emory University; Roy Sutliff, Emory University; Jennifer L Ingram, Duke University; Soma S.S.K Jyothula, University of Texas, Houston; Rajarajan A Thandavarayan, Houston Methodist Hospital; Howard J Huang, Houston Methodist Hospital; Eva S Nozik, University of Colorado Anschutz; Eric J Wagner, University of Rochester; C. Michael Hart, Emory University; Harry Karmouty-Quintana, University of Texas, Houston
• Language: English
• Date: 2022-06-10
• Publisher: ELSEVIER
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2024 Elsevier B.V.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.matbio.2022.06.001
• Title of Journal or Parent Work: MATRIX BIOLOGY
• Volume: 111
• Start Page: 53
• End Page: 75
• Grant/Funding Information: This work was supported by NHLBI 5T32HL116271 and the Actelion Pharmaceuticals Young Investigator Award to VT; VA Merit Review Award 1I01BX004263 to CMH; NHLBI 5R01HL102167 to CMH and RLS; NHLBI 5R01HL133053 to BYK, NHLBI 5R01HL138510 to HKQ; NHLBI 5R01HL086680 and 1R35HL139726-01 to ENG. Portions of this work were previously presented at scientific symposia.
• Keywords: Life Sciences & Biomedicine; PHARMACOKINETICS; Cell Biology; 4-METHYLUMBELLIFERONE; VASOCONSTRICTION; Science & Technology; Biochemistry & Molecular Biology; HYPOXIA; ALTERNATIVE POLYADENYLATION; INHIBITION; OXIDE-MEDIATED RELAXATION; INFLAMMATION; MITOCHONDRIAL-FUNCTION; PROLIFERATION
• Research Categories: Biology, Cell; Chemistry, Biochemistry; Health Sciences, Dentistry; Biology, Molecular

Abstract

Pulmonary hypertension (PH) comprises a diverse group of disorders that share a common pathway of pulmonary vascular remodeling leading to right ventricular failure. Development of anti-remodeling strategies is an emerging frontier in PH therapeutics that requires a greater understanding of the interactions between vascular wall cells and their extracellular matrices. The ubiquitous matrix glycan, hyaluronan (HA), is markedly elevated in lungs from patients and experimental models with PH. Herein, we identified HA synthase-2 (HAS2) in the pulmonary artery smooth muscle cell (PASMC) layer as a predominant locus of HA dysregulation. HA upregulation involves depletion of NUDT21, a master regulator of alternative polyadenylation, resulting in 3’UTR shortening and hyper-expression of HAS2. The ensuing increase of HAS2 and hyper-synthesis of HA promoted bioenergetic dysfunction of PASMC characterized by impaired mitochondrial oxidative capacity and a glycolytic shift. The resulting HA accumulation stimulated pro-remodeling phenotypes such as cell proliferation, migration, apoptosis-resistance, and stimulated pulmonary artery contractility. Transgenic mice, mimicking HAS2 hyper-synthesis in smooth muscle cells, developed spontaneous PH, whereas targeted deletion of HAS2 prevented experimental PH. Pharmacological blockade of HAS2 restored normal bioenergetics in PASMC, ameliorated cell remodeling phenotypes, and reversed experimental PH in vivo. In summary, our results uncover a novel mechanism of HA hyper-synthesis and downstream effects on pulmonary vascular cell metabolism and remodeling.