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A Novel Protective Role for Matrix Metalloproteinase-8 in the Pulmonary Vasculature
- Source :
- American journal of respiratory and critical care medicine. 204(12)
- Publication Year :
- 2021
-
Abstract
- Rationale: Mechanical signaling through cell-matrix interactions plays a major role in progressive vascular remodeling in pulmonary arterial hypertension (PAH). Matrix metalloproteinase-8 (MMP-8) is an interstitial collagenase involved in regulating inflammation and fibrosis of the lung and systemic vasculature, but its role in PAH pathogenesis remains unexplored. Objectives: To evaluate MMP-8 as a modulator of pathogenic mechanical signaling in PAH. Methods: MMP-8 levels were measured in plasma from pulmonary hypertension (PH) patients and controls by ELISA. MMP-8 vascular expression was examined in lung tissue from PAH patients and rodent models of PH. MMP-8-/- and MMP-8+/+ mice were exposed to normobaric hypoxia or normoxia for 4-8 weeks. PH severity was evaluated by right ventricular systolic pressure (RVSP), echocardiography, pulmonary artery (PA) morphometry and immunostaining. Proliferation, migration, matrix component expression, and mechanical signaling were assessed in MMP-8-/- and MMP-8+/+ pulmonary artery smooth muscle cells (PASMCs). Measurements and Main Results: MMP-8 expression was significantly increased in plasma and PAs of PH patients compared to controls and induced in the pulmonary vasculature in rodent PH models. Hypoxia-exposed MMP-8-/- mice had significant mortality, increased RVSP, severe RV dysfunction, and exaggerated vascular remodeling compared to MMP-8+/+ mice. MMP-8-/- PASMCs demonstrated exaggerated proliferation and migration mediated by altered matrix protein expression, elevated integrin-β3 levels, and induction of focal adhesion kinase (FAK) and downstream Yes-associated protein/Transcriptional coactivator with PDZ-binding motif (YAP/TAZ) activity. Conclusions: MMP-8 is a novel protective factor upregulated in the pulmonary vasculature during PAH pathogenesis. MMP-8 opposes pathologic mechanobiological feedback by altering matrix composition and disrupting integrin-β3/FAK and YAP/TAZ-dependent mechanical signaling in PASMCs.
- Subjects :
- Pulmonary and Respiratory Medicine
Adult
Male
medicine.medical_specialty
Inflammation
Enzyme-Linked Immunosorbent Assay
Matrix metalloproteinase
Pulmonary Artery
Vascular Remodeling
Critical Care and Intensive Care Medicine
Pathogenesis
Rats, Sprague-Dawley
Mice
Fibrosis
Internal medicine
medicine.artery
Medicine
Animals
Humans
Aged
Mice, Knockout
Pulmonary Arterial Hypertension
Lung
business.industry
Middle Aged
medicine.disease
Pulmonary hypertension
Rats
Up-Regulation
Mice, Inbred C57BL
Endocrinology
medicine.anatomical_structure
Matrix Metalloproteinase 8
Case-Control Studies
Pulmonary artery
Interstitial collagenase
Female
medicine.symptom
business
Biomarkers
Subjects
Details
- ISSN :
- 15354970
- Volume :
- 204
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- American journal of respiratory and critical care medicine
- Accession number :
- edsair.doi.dedup.....a06006f193a3443f4e24b117d94e2b81