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

Tseng, Victor

Collum, Scott D

Allawzi, Ayed

Crotty, Kathryn

Yeligar, Samantha

Trammell, Aaron

Ryan Smith, M

Kang, Bum-Yong

Sutliff, Roy L

Ingram, Jennifer L

Jyothula, Soma SSK

Thandavarayan, Rajarajan A

Huang, Howard J

Nozik, Eva S

Wagner, Eric J

Michael Hart, C

Karmouty-Quintana, Harry

2022-07-01T14:17:22Z

2022-07-01T14:17:22Z

2022-06-04

2022-07-01T14:17:21Z

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.

S0945-053X(22)00075-0

0945-053X

1569-1802

https://hdl.handle.net/10161/25429

eng

Elsevier BV

Matrix biology : journal of the International Society for Matrix Biology

10.1016/j.matbio.2022.06.001

Hyaluronan

Pulmonary hypertension

RNA processing deficiency

Vascular biology

extracellular matrix

hypoxia

metabolism

smooth muscle cell

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

Journal article

Ingram, Jennifer L|0000-0002-5269-8864

S0945-053X(22)00075-0

Duke

School of Medicine

Clinical Science Departments

Medicine

Pathology

Surgery

Medicine, Pulmonary, Allergy, and Critical Care Medicine

Surgery, Surgical Sciences

Published

111