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

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.

SUBMITTER: Tseng V

PROVIDER: S-EPMC9676077 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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

Tseng Victor V Collum Scott D SD Allawzi Ayed A Crotty Kathryn K Yeligar Samantha S Trammell Aaron A Ryan Smith M M Kang Bum-Yong BY Sutliff Roy L RL Ingram Jennifer L JL Jyothula Soma S S K SSSK Thandavarayan Rajarajan A RA Huang Howard J HJ Nozik Eva S ES Wagner Eric J EJ Michael Hart C C Karmouty-Quintana Harry H

Matrix biology : journal of the International Society for Matrix Biology 20220604

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. Herei ...[more]

PMID: 35671866

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Project description:BackgroundMitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species (ROS) generation, results in lipid peroxidation-induced ferroptosis. Ferroptosis is an inflammatory mode of cell death as it both promotes complement activation and recruits macrophages. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells exhibit disrupted lipid metabolism and increased ROS production, and there is ectopic complement deposition and inflammatory macrophage accrual in the surrounding vasculature. However, the integrative effects of ferroptosis on metabolism, cellular landscape changes in the lung, complement induction, and pulmonary vascular remodeling are unknown.MethodsMulti-omics analyses in rodents and a genetic association study in humans evaluated the role of ferroptosis in PAH.ResultsFerrostatin-1, a small-molecule ferroptosis inhibitor, mitigated PAH severity and improved right ventricular function in monocrotaline rats. RNA-seq and proteomics analyses demonstrated ferroptosis was induced with increasingly severe PAH. Metabolomics and proteomics data showed ferroptosis inhibition restructured lung metabolism and altered phosphatidylcholine and phosphatidylethanolamine levels. RNA-seq, proteomics, and confocal microscopy revealed complement activation and pro-inflammatory cytokines/chemokines were suppressed by ferrostatin-1. Additionally, ferrostatin-1 combatted changes in endothelial, smooth muscle, and interstitial macrophage abundances and gene activation patterns in the lungs as revealed by deconvolution RNA-seq. Finally, the presence of six single-nucleotide polymorphisms in ferroptosis genes were independently associated with pulmonary hypertension severity in the Vanderbilt BioVU repository.ConclusionsRodent and human data nominate ferroptosis as a PAH regulating pathway via its ability to modulate lung lipid metabolism, repress pathogenic complement activation, dampen interstitial macrophage infiltration, and restore the lung cellular environment.

Dataset Information

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

Publications

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

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