| Autor: |
Taylor S; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Stanford Cardiovascular Institute.; Department of Pediatrics - Cardiology., Isobe S; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Stanford Cardiovascular Institute.; Department of Pediatrics - Cardiology., Cao A; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Stanford Cardiovascular Institute.; Department of Pediatrics - Cardiology., Contrepois K; Stanford Cardiovascular Institute.; Department of Genetics., Benayoun BA; Leonard Davis School of Gerontology and.; Department of Molecular and Computational Biology, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California., Jiang L; Stanford Cardiovascular Institute.; Department of Genetics., Wang L; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Stanford Cardiovascular Institute.; Department of Pediatrics - Cardiology., Melemenidis S; Department of Radiation Oncology., Ozen MO; Department of Radiology Canary Center for Cancer Early Detection., Otsuki S; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Stanford Cardiovascular Institute.; Department of Pediatrics - Cardiology., Shinohara T; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Stanford Cardiovascular Institute.; Department of Pediatrics - Cardiology., Sweatt AJ; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Department of Medicine - Pulmonary and Critical Care Medicine, and., Kaplan J; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Stanford Cardiovascular Institute.; Department of Pediatrics - Cardiology., Moonen JR; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Stanford Cardiovascular Institute.; Department of Pediatrics - Cardiology., Marciano DP; Stanford Cardiovascular Institute.; Department of Genetics., Gu M; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Stanford Cardiovascular Institute.; Department of Pediatrics - Cardiology., Miyagawa K; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Stanford Cardiovascular Institute.; Department of Pediatrics - Cardiology., Hayes B; Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, California., Sierra RG; Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, California., Kupitz CJ; Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, California., Del Rosario PA; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Department of Medicine - Pulmonary and Critical Care Medicine, and., Hsi A; Vera Moulton Wall Center for Pulmonary Vascular Diseases., Thompson AAR; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Stanford Cardiovascular Institute.; Department of Pediatrics - Cardiology.; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom; and., Ariza ME; Department of Cancer Biology and Genetics and.; Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, Ohio., Demirci U; Department of Radiation Oncology., Zamanian RT; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Department of Medicine - Pulmonary and Critical Care Medicine, and., Haddad F; Stanford Cardiovascular Institute.; Department of Medicine - Cardiovascular Medicine, Stanford University, Stanford, California., Nicolls MR; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Stanford Cardiovascular Institute.; Department of Medicine - Pulmonary and Critical Care Medicine, and., Snyder MP; Stanford Cardiovascular Institute.; Department of Genetics., Rabinovitch M; Vera Moulton Wall Center for Pulmonary Vascular Diseases.; Stanford Cardiovascular Institute.; Department of Pediatrics - Cardiology. |
| Abstrakt: |
Rationale: The role of neutrophils and their extracellular vesicles (EVs) in the pathogenesis of pulmonary arterial hypertension is unclear. Objectives: To relate functional abnormalities in pulmonary arterial hypertension neutrophils and their EVs to mechanisms uncovered by proteomic and transcriptomic profiling. Methods: Production of elastase, release of extracellular traps, adhesion, and migration were assessed in neutrophils from patients with pulmonary arterial hypertension and control subjects. Proteomic analyses were applied to explain functional perturbations, and transcriptomic data were used to find underlying mechanisms. CD66b-specific neutrophil EVs were isolated from plasma of patients with pulmonary arterial hypertension, and we determined whether they produce pulmonary hypertension in mice. Measurements and Main Results: Neutrophils from patients with pulmonary arterial hypertension produce and release increased neutrophil elastase, associated with enhanced extracellular traps. They exhibit reduced migration and increased adhesion attributed to elevated β1-integrin and vinculin identified by proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic IFN signature that we related to an increase in human endogenous retrovirus K envelope protein. Transfection of human endogenous retrovirus K envelope in a neutrophil cell line (HL-60) increases neutrophil elastase and IFN genes, whereas vinculin is increased by human endogenous retrovirus K deoxyuridine triphosphate diphosphatase that is elevated in patient plasma. Neutrophil EVs from patient plasma contain increased neutrophil elastase and human endogenous retrovirus K envelope and induce pulmonary hypertension in mice, mitigated by elafin, an elastase inhibitor. Conclusions: Elevated human endogenous retroviral elements and elastase link a neutrophil innate immune response to pulmonary arterial hypertension. |
