A Novel Protective Role for Matrix Metalloproteinase-8 in the Pulmonary Vasculature
Paul B. Dieffenbach, Christina Mallarino Haeger, Rakhshinda Rehman, Alexis M. Corcoran, Anna Maria F. Coronata, Shamsudheen K. Vellarikkal, Izabela Chrobak, Aaron B. Waxman, Sally H. Vitali, Lynette M. Sholl, Robert F. Padera, David Lagares, Francesca Polverino, Caroline A. Owen, Laura E. Fredenburgh
Abstract
Abstract Rationale Mechanical signaling through cell–matrix interactions plays a major role in progressive vascular remodeling in pulmonary arterial hypertension (PAH). MMP-8 (matrix metalloproteinase-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 patients with pulmonary hypertension (PH) and controls by ELISA. MMP-8 vascular expression was examined in lung tissue from patients with PAH 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, echocardiography, pulmonary artery 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 pulmonary arteries of patients with PH compared with controls and induced in the pulmonary vasculature in rodent PH models. Hypoxia-exposed MMP-8–/– mice had significant mortality, increased right ventricular systolic pressure, severe right ventricular dysfunction, and exaggerated vascular remodeling compared with MMP-8+/+ mice. MMP-8–/– PASMCs demonstrated exaggerated proliferation and migration mediated by altered matrix protein expression, elevated integrin-β3 levels, and induction of FAK (focal adhesion kinase) and downstream YAP (Yes-associated protein)/TAZ (transcriptional coactivator with PDZ-binding motif) 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.