CYLD mediates human pulmonary artery smooth muscle cell dysfunction in congenital heart disease‐associated pulmonary arterial hypertension
- 28 January 2021
- journal article
- research article
- Published by Wiley in Journal of Cellular Physiology
- Vol. 236 (9), 6297-6311
- https://doi.org/10.1002/jcp.30298
Abstract
Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease (CHD). Deubiquitinase cylindromatosis (CYLD) has been reported to significantly aggravate vascular smooth muscle cell (VSMC) phenotypic transformation, proliferation, and migration. Here, we aimed to further investigate its roles and underlying mechanisms in the CHD‐PAH development. The expression of CYLD in the lung tissues from CHD‐PAH patients and monocrotaline (MCT) plus aortocaval (AV)‐induced PAH rats, pulmonary artery smooth muscle cells (PASMCs) from MCT‐AV‐induced PAH rats, and human PASMCs (HPASMCs) was evaluated. After infection with CYLD siRNA or pcNDA3.1‐CYLD, the proliferation, migration, and apoptosis of HPASMCs were measured using an EdU assay, transwell and scratch wound healing assays, and flow cytometric assay, respectively. An adeno‐associated virus (AAV) vector encoding CYLD was used to suppress CYLD expression by being intratracheally instilled in rats 7 days before MCT‐AV treatment. The results showed that CYLD was increased in the lung tissues from CHD‐PAH patients and MCT‐AV‐induced PAH rats, and in PASMCs from MCT‐AV‐induced PAH rats. The contractile‐type HPASMCs expressed low levels of CYLD, while the proliferative synthetic‐type HPASMCs expressed high levels of CYLD. In addition, CYLD could mediate HPASMC dysfunction, which regulated HPASMC phenotypic transformation and proliferation via the modulation of p38 and ERK activation, while CYLD regulated HPASMC migration via the modulation of p38 activation. In vivo results demonstrated that the local suppression of CYLD expression could attenuate the increased levels of PAH and its associated pulmonary vascular remodeling in MCT‐AV‐induced PAH rats. Collectively, these results indicated that CYLD might be a potential novel therapeutic target for the prevention of PAH and pulmonary vascular remodeling in CHD‐PAH through the modulation of HPASMC dysfunction.Funding Information
- China Postdoctoral Science Foundation (2019M650574)
- National Natural Science Foundation of China (8177021278)
This publication has 37 references indexed in Scilit:
- Fibrosis of pulmonary vascular remodeling in carotid artery-jugular vein shunt pulmonary artery hypertension model of ratsEuropean Journal of Cardio-Thoracic Surgery, 2011
- Serum Response Factor Controls CYLD Expression via MAPK Signaling PathwayPLOS ONE, 2011
- Combination of sildenafil and simvastatin ameliorates monocrotaline-induced pulmonary hypertension in ratsPulmonary Pharmacology & Therapeutics, 2010
- CYLD Tidies Up Dishevelled SignalingMolecular Cell, 2010
- Naturally occurring short splice variant of CYLD positively regulates dendritic cell functionBlood, 2009
- Potential Role of CYLD (Cylindromatosis) as a Deubiquitinating Enzyme in Vascular CellsThe American Journal of Pathology, 2008
- Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD The Journal of Experimental Medicine, 2007
- Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responsesThe Journal of Experimental Medicine, 2007
- Capacitative calcium entry and TRPC channel proteins are expressed in rat distal pulmonary arterial smooth muscleAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2004
- The Pathology of Hypertensive Pulmonary Vascular DiseaseCirculation, 1958