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Lysyl oxidases play a causal role in vascular remodeling in clinical and experimental pulmonary arterial hypertension.
Lysyl oxidases play a causal role in vascular remodeling in clinical and experimental pulmonary arterial hypertension.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2014 Jul; Vol. 34 (7), pp. 1446-58. Date of Electronic Publication: 2014 May 15. - Publication Year :
- 2014
-
Abstract
- Objective: Pulmonary vascular remodeling, the pathological hallmark of pulmonary arterial hypertension, is attributed to proliferation, apoptosis resistance, and migration of vascular cells. A role of dysregulated matrix cross-linking and stability as a pathogenic mechanism has received little attention. We aimed to assess whether matrix cross-linking enzymes played a causal role in experimental pulmonary hypertension (PH).<br />Approach and Results: All 5 lysyl oxidases were detected in concentric and plexiform vascular lesions of patients with idiopathic pulmonary arterial hypertension. Lox, LoxL1, LoxL2, and LoxL4 expression was elevated in lungs of patients with idiopathic pulmonary arterial hypertension, whereas LoxL2 and LoxL3 expression was elevated in laser-capture microdissected vascular lesions. Lox expression was hypoxia-responsive in pulmonary artery smooth muscle cells and adventitial fibroblasts, whereas LoxL1 and LoxL2 expression was hypoxia-responsive in adventitial fibroblasts. Lox expression was increased in lungs from hypoxia-exposed mice and in lungs and pulmonary artery smooth muscle cells of monocrotaline-treated rats, which developed PH. Pulmonary hypertensive mice exhibited increased muscularization and perturbed matrix structures in vessel walls of small pulmonary arteries. Hypoxia exposure led to increased collagen cross-linking, by dihydroxylysinonorleucine and hydroxylysinonorleucine cross-links. Administration of the lysyl oxidase inhibitor β-aminopropionitrile attenuated the effect of hypoxia, limiting perturbations to right ventricular systolic pressure, right ventricular hypertrophy, and vessel muscularization and normalizing collagen cross-linking and vessel matrix architecture.<br />Conclusions: Lysyl oxidases are dysregulated in clinical and experimental PH. Lysyl oxidases play a causal role in experimental PH and represent a candidate therapeutic target. Our proof-of-principle study demonstrated that modulation of lung matrix cross-linking can affect pulmonary vascular remodeling associated with PH.<br /> (© 2014 American Heart Association, Inc.)
- Subjects :
- Adult
Aged, 80 and over
Animals
Antihypertensive Agents pharmacology
Case-Control Studies
Cell Hypoxia
Cells, Cultured
Collagen metabolism
Disease Models, Animal
Elastin metabolism
Enzyme Inhibitors pharmacology
Familial Primary Pulmonary Hypertension
Female
Fibroblasts enzymology
Fibroblasts pathology
Gene Expression Regulation, Enzymologic
Humans
Hypertension, Pulmonary drug therapy
Hypertension, Pulmonary etiology
Hypertension, Pulmonary genetics
Hypertension, Pulmonary pathology
Hypertrophy, Right Ventricular enzymology
Hypertrophy, Right Ventricular etiology
Hypertrophy, Right Ventricular prevention & control
Hypoxia complications
Isoenzymes
Male
Mice
Middle Aged
Monocrotaline
Muscle, Smooth, Vascular enzymology
Muscle, Smooth, Vascular pathology
Myocytes, Smooth Muscle enzymology
Myocytes, Smooth Muscle pathology
Protein-Lysine 6-Oxidase antagonists & inhibitors
Protein-Lysine 6-Oxidase genetics
Pulmonary Artery drug effects
Pulmonary Artery pathology
RNA, Messenger metabolism
Rats
Ventricular Dysfunction, Right enzymology
Ventricular Dysfunction, Right etiology
Ventricular Dysfunction, Right physiopathology
Ventricular Dysfunction, Right prevention & control
Young Adult
Hypertension, Pulmonary enzymology
Protein-Lysine 6-Oxidase metabolism
Pulmonary Artery enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 34
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 24833797
- Full Text :
- https://doi.org/10.1161/ATVBAHA.114.303534