NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension

Sci Transl Med. 2018 Jun 13;10(445):eaap7294. doi: 10.1126/scitranslmed.aap7294.

Andriy O Samokhin ¹, Thomas Stephens ¹, Bradley M Wertheim ¹ ², Rui-Sheng Wang ³, Sara O Vargas ⁴, Lai-Ming Yung ⁵, Minwei Cao ¹, Marcel Brown ¹, Elena Arons ¹, Paul B Dieffenbach ², Jason G Fewell ⁶, Majed Matar ⁶, Frederick P Bowman ¹, Kathleen J Haley ², George A Alba ⁷, Stefano M Marino ⁸ ⁹, Rahul Kumar ¹⁰, Ivan O Rosas ², Aaron B Waxman ², William M Oldham ², Dinesh Khanna ¹¹, Brian B Graham ¹⁰, Sachiko Seo ¹², Vadim N Gladyshev ⁸, Paul B Yu ⁵, Laura E Fredenburgh ², Joseph Loscalzo ¹ ⁵, Jane A Leopold ⁵, Bradley A Maron ¹³

Affiliations

1 Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
2 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
3 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
4 Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
5 Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
6 Celsion Corporation, Lawrenceville, NJ 08648, USA.
7 Department of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
8 Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
9 Department of Biotechnology, Akdeniz University, Konyaaltı, Antalya 07058, Turkey.
10 Program in Translational Lung Research, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
11 Division of Rheumatology, University of Michigan Scleroderma Program, Ann Arbor, MI 48109, USA.
12 Department of Hematology and Oncology, National Cancer Research Center East, Kashiwa-shi, Chiba-ken 277-8577, Japan.
13 Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. bmaron@bwh.harvard.edu.

PMID: 29899023 DOI: 10.1126/scitranslmed.aap7294

Abstract

Germline mutations involving small mothers against decapentaplegic-transforming growth factor-β (SMAD-TGF-β) signaling are an important but rare cause of pulmonary arterial hypertension (PAH), which is a disease characterized, in part, by vascular fibrosis and hyperaldosteronism (ALDO). We developed and analyzed a fibrosis protein-protein network (fibrosome) in silico, which predicted that the SMAD3 target neural precursor cell expressed developmentally down-regulated 9 (NEDD9) is a critical ALDO-regulated node underpinning pathogenic vascular fibrosis. Bioinformatics and microscale thermophoresis demonstrated that oxidation of Cys¹⁸ in the SMAD3 docking region of NEDD9 impairs SMAD3-NEDD9 protein-protein interactions in vitro. This effect was reproduced by ALDO-induced oxidant stress in cultured human pulmonary artery endothelial cells (HPAECs), resulting in impaired NEDD9 proteolytic degradation, increased NEDD9 complex formation with NK2 homeobox 5 (NKX2-5), and increased NKX2-5 binding to COL3A1 Up-regulation of NEDD9-dependent collagen III expression corresponded to changes in cell stiffness measured by atomic force microscopy. HPAEC-derived exosomal signaling targeted NEDD9 to increase collagen I/III expression in human pulmonary artery smooth muscle cells, identifying a second endothelial mechanism regulating vascular fibrosis. ALDO-NEDD9 signaling was not affected by treatment with a TGF-β ligand trap and, thus, was not contingent on TGF-β signaling. Colocalization of NEDD9 with collagen III in HPAECs was observed in fibrotic pulmonary arterioles from PAH patients. Furthermore, NEDD9 ablation or inhibition prevented fibrotic vascular remodeling and pulmonary hypertension in animal models of PAH in vivo. These data identify a critical TGF-β-independent posttranslational modification that impairs SMAD3-NEDD9 binding in HPAECs to modulate vascular fibrosis and promote PAH.

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