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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Tseng, V; Collum, SD; Allawzi, A; Crotty, K; Yeligar, S; Trammell, A; Ryan Smith, M; Kang, B-Y; Sutliff, RL; Ingram, JL; Jyothula, SSSK; Thandavarayan, RA; Huang, HJ; Nozik, ES; Wagner, EJ; Michael Hart, C; Karmouty-Quintana, H

Published Date

  • August 2022

Published In

Volume / Issue

  • 111 /

Start / End Page

  • 53 - 75

PubMed ID

  • 35671866

Pubmed Central ID

  • PMC9676077

Electronic International Standard Serial Number (EISSN)

  • 1569-1802

Digital Object Identifier (DOI)

  • 10.1016/j.matbio.2022.06.001


  • eng

Conference Location

  • Netherlands