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

Publication ,  Journal Article
Tseng, V; Collum, SD; Allawzi, A; Crotty, K; Yeligar, S; Trammell, A; Ryan Smith, M; Kang, B-Y; Sutliff, RL; Ingram, JL; Jyothula, SSSK ...
Published in: Matrix Biol
August 2022

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.

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Published In

Matrix Biol

DOI

EISSN

1569-1802

Publication Date

August 2022

Volume

111

Start / End Page

53 / 75

Location

Netherlands

Related Subject Headings

  • Myocytes, Smooth Muscle
  • Mice, Transgenic
  • Mice
  • Hypertension, Pulmonary
  • Hyaluronic Acid
  • Hyaluronan Synthases
  • Humans
  • Energy Metabolism
  • Cell Proliferation
  • Biochemistry & Molecular Biology
 

Citation

APA
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ICMJE
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Tseng, V., Collum, S. D., Allawzi, A., Crotty, K., Yeligar, S., Trammell, A., … Karmouty-Quintana, H. (2022). 3'UTR shortening of HAS2 promotes hyaluronan hyper-synthesis and bioenergetic dysfunction in pulmonary hypertension. Matrix Biol, 111, 53–75. https://doi.org/10.1016/j.matbio.2022.06.001
Tseng, Victor, Scott D. Collum, Ayed Allawzi, Kathryn Crotty, Samantha Yeligar, Aaron Trammell, M. Ryan Smith, et al. “3'UTR shortening of HAS2 promotes hyaluronan hyper-synthesis and bioenergetic dysfunction in pulmonary hypertension.Matrix Biol 111 (August 2022): 53–75. https://doi.org/10.1016/j.matbio.2022.06.001.
Tseng V, Collum SD, Allawzi A, Crotty K, Yeligar S, Trammell A, et al. 3'UTR shortening of HAS2 promotes hyaluronan hyper-synthesis and bioenergetic dysfunction in pulmonary hypertension. Matrix Biol. 2022 Aug;111:53–75.
Tseng, Victor, et al. “3'UTR shortening of HAS2 promotes hyaluronan hyper-synthesis and bioenergetic dysfunction in pulmonary hypertension.Matrix Biol, vol. 111, Aug. 2022, pp. 53–75. Pubmed, doi:10.1016/j.matbio.2022.06.001.
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. 3'UTR shortening of HAS2 promotes hyaluronan hyper-synthesis and bioenergetic dysfunction in pulmonary hypertension. Matrix Biol. 2022 Aug;111:53–75.
Journal cover image

Published In

Matrix Biol

DOI

EISSN

1569-1802

Publication Date

August 2022

Volume

111

Start / End Page

53 / 75

Location

Netherlands

Related Subject Headings

  • Myocytes, Smooth Muscle
  • Mice, Transgenic
  • Mice
  • Hypertension, Pulmonary
  • Hyaluronic Acid
  • Hyaluronan Synthases
  • Humans
  • Energy Metabolism
  • Cell Proliferation
  • Biochemistry & Molecular Biology