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

Victor Tseng, Scott D. Collum, Ayed Allawzi, Kathryn Crotty, Samantha Yeligar, Aaron Trammell, M. Ryan Smith, Bum Yong Kang, Roy L. Sutliff, Jennifer L. Ingram, Soma S.S.K. Jyothula, Rajarajan A. Thandavarayan, Howard J. Huang, Eva S. Nozik, Eric J. Wagner, C. Michael Hart, Harry Karmouty-Quintana

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)53-75
Number of pages23
JournalMatrix Biology
Volume111
DOIs
StatePublished - Aug 2022

Keywords

  • 3' Untranslated Regions/genetics
  • Animals
  • Cell Proliferation
  • Energy Metabolism/genetics
  • Humans
  • Hyaluronan Synthases/genetics
  • Hyaluronic Acid/biosynthesis
  • Hypertension, Pulmonary/enzymology
  • Mice
  • Mice, Transgenic
  • Myocytes, Smooth Muscle/enzymology
  • hypoxia
  • smooth muscle cell
  • RNA processing deficiency
  • Pulmonary hypertension
  • Vascular biology
  • Hyaluronan
  • metabolism
  • extracellular matrix

ASJC Scopus subject areas

  • Molecular Biology

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