elastin and Familial-Primary-Pulmonary-Hypertension

We determined in patients with pulmonary arterial (PA) hypertension (PAH) whether in addition to increased production of elastase by PA smooth muscle cells previously reported, PA elastic fibers are susceptible to degradation because of their abnormal assembly.. Fibrillin-1 and elastin are the major components of elastic fibers, and fibrillin-1 binds bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β1 (TGFβ1). Thus, we considered whether BMPs like TGFβ1 contribute to elastic fiber assembly and whether this process is perturbed in PAH particularly when the BMP receptor, BMPR2, is mutant. We also assessed whether in mice with. Disrupting BMPR2 impairs TGFβ1- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH.

Topics: Animals; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Protein Receptors, Type II; Case-Control Studies; Cells, Cultured; Disease Models, Animal; Elastic Tissue; Elastin; Familial Primary Pulmonary Hypertension; Fibrillin-1; Fibroblasts; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mutation; Myocytes, Smooth Muscle; Phenotype; Pulmonary Artery; RNA Interference; Transfection; Transforming Growth Factor beta; Vascular Remodeling

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).. 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.. 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.

Topics: Adult; Aged, 80 and over; Animals; Antihypertensive Agents; Case-Control Studies; Cell Hypoxia; Cells, Cultured; Collagen; Disease Models, Animal; Elastin; Enzyme Inhibitors; Familial Primary Pulmonary Hypertension; Female; Fibroblasts; Gene Expression Regulation, Enzymologic; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Isoenzymes; Male; Mice; Middle Aged; Monocrotaline; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Protein-Lysine 6-Oxidase; Pulmonary Artery; Rats; RNA, Messenger; Ventricular Dysfunction, Right; Young Adult