Abstract 19526: Pathological Vascular Remodeling in Pulmonary Hypertension: A Role for Perturbed Matrix Cross-Linking?
Introduction: Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling and arterial stiffness. We hypothesize that excessive cross-linking of the vascular matrix, as a consequence of dysregulated expression of matrix cross-linking enzymes, may contribute to the vascular lesions observed in affected lungs.
Methods: The expression of three families of matrix cross-linking enzymes: the lysyl oxidase (Lox), transglutaminase (Tgm), and the procollagen-lysine 1,2-oxoglutarate 5 dioxygenase (Plod) families was assessed by real-time PCR and immunoblot, in hypertensive (and control) mouse and human lungs, laser-capture microdissection (LCM) of small pulmonary arteries, and in isolated pulmonary artery smooth muscle cells (PASMC) and fibroblasts exposed to hypoxia. The lysyl oxidase inhibitor beta-aminopropionitrile was applied in the hypoxia mouse model of PAH.
Results: An increase in mRNA expression of several matrix cross-linking enzymes was seen in lungs of human patients (n = 8/group) with PAH (fold change: Lox: 9.1; LoxL1: 3.9; Tgm1: 17.1; Plod1: 3.5; Plod2: 3.6) and in lungs of mice (n = 12/ group) with hypoxia-induced PAH (Lox: 6.2-fold; Tgm2: 2.0-fold). Trends were confirmed by immunoblot and activity assay. Lox and Plod1 were induced by hypoxia in pulmonary arteries of mice after 3 h, and in lung fibroblasts and PASMCs (>3 fold; n = 4/group) in vitro. Lox, LoxL2, Plod1 and Tgm2 expression was also elevated (>3 fold) in microdissected small pulmonary arteries from patients with PAH. PAH and vascular remodeling were attenuated by pre-treatment of mice with beta-aminopropionitrile. Discussion: Here we report the exciting observation that the expression of matrix cross-linking enzymes is elevated in the pulmonary vasculature of humans with PAH, and mice with hypoxia-induced PAH. Our data suggest that hypoxia may drive this elevated gene expression. Parallel trends in humans and in an animal model of human disease makes a strong case for a role for dysregulated matrix cross-linking in PAH. Our working hypothesis is that excessive cross-linking of the vascular matrix may contribute, at least in part, to the perturbed arterial morphology, most notably, vascular wall elasticity and stiffness, in affected lungs.
- © 2010 by American Heart Association, Inc.