title: The enzymatic degradation of hyaluronan is associated with disease progression in experimental pulmonary hypertension.
abstract: Hyaluronan (HA) degradation fragments have been linked to inflammation in a wide range of lung diseases. In idiopathic pulmonary arterial hypertension, HA accumulation has been associated with advanced disease. In this study, we investigated the potential role of HA degradation in the early stages of disease by examining HA distribution, molecular mass, synthesis, and enzymatic degradation at different stages of disease progression in a rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH). At 28 days post-MCT, severe PH was associated with increased total lung HA (P = 0.04). In contrast, a significant decrease in total lung HA was observed on day 10, before the onset of PH (P = 0.02). Molecular mass analysis revealed a loss of high molecular mass (HMM) HA at 10 and 24 days post-MCT, followed by an increase in HMM HA at 28 days. Expression of HA synthase 2 (HAS2) was elevated in MCT-challenged animals at 24 and 28 days, consistent with increased synthesis of HMM HA. Analysis by Morgan Elson assay and zymography demonstrated increased hyaluronidase-1 activity in the lungs of MCT-challenged rats, indicating that the observed increases in HAS2 expression and HA synthesis were counterbalanced, in part, by enhanced degradation. The present data demonstrate that, in the MCT model, early-stage PH is associated with enhanced hyaluronidase-1 activity, while both degradation and synthesis are increased at later stages. Thus an early increase in the generation of proinflammatory HA fragments may play a role in the onset and progression of pulmonary arterial hypertension.
authors.affiliation: Terrence Donnelly Cardiovascular Research Laboratories, Rm. 8-038, Queen Wing, St. Michael's Hospital, 30 Bond St., Toronto, Ontario, M5B 1W8 Canada.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Ormiston
authors.forename: Graham R D
authors.initials: GR
authors.lastname: Slaughter
authors.forename: Yupu
authors.initials: Y
authors.lastname: Deng
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: David W
authors.initials: DW
authors.lastname: Courtman
mesh_terms: D000818:Animals; D018450:Disease Progression; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000235:genetics / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008970:Molecular Weight; D016686:Monocrotaline / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D016686:Monocrotaline; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases; D006821:Hyaluronoglucosaminidase