Elastase and cell matrix interactions in the pathobiology of vascular disease.
Ultrastructural observations in lung tissue implicated an endogenous vascular elastase (EVE), in the pathobiology of pulmonary vascular disease. In experimental rats, increased activity of a 20 kDa serine proteinase related to adipsin precedes the development of sustained pulmonary hypertension and vascular abnormalities. A further increase in activity is related to malignant progression of the disease. A cause and effect relationship was suggested by studies in which elastase inhibitors successfully prevented or retarded progression of pulmonary hypertension. In vitro studies have shown that both serum and endothelial factors induce EVE via tyrosine kinase intracellular signalling. Induction of EVE can release basic fibroblast growth factor from the extracellular matrix in an active form stimulating smooth muscle cell proliferation. Elastase activity was also observed in the process of smooth muscle cell migration and neointimal formation in coronary arteries following experimental cardiac transplantation. An immune/inflammatory response is observed with increased production of cytokines, tumor necrosis factor-alpha and interleukin (IL)-1 beta, reciprocally up-regulating production of fibronectin, a glycoprotein which mediated smooth muscle cell migration. The action of IL-1 beta in inducing fibronectin is facilitated by the production of elastin peptides generated by increased activity of an elastase in the coronary arteries. Our studies suggest that ligation of the elastin binding protein by elastin peptides unmasks IL-1 receptors. Fibronectin also stimulates transendothelial migration of lymphocytes which perpetuates the inflammatory response leading to neointimal formation in this model. Masking integrins on T cells with a decoy synthetic CS-1 (fibronectin) peptide largely prevented transendothelial migration and coronary neointimal formation following cardiac transplant.
Rabinovitch
M
M
Division of Cardiovascular Research, University of Toronto, Ontario, Canada.
D000818:Animals; D004730:Endothelium, Vascular / Q000473:pathology* / Q000503:physiopathology*; D005353:Fibronectins / Q000502:physiology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000503:physiopathology; D010196:Pancreatic Elastase / Q000502:physiology*; D011651:Pulmonary Artery / Q000473:pathology; D051381:Rats; D014652:Vascular Diseases / Q000473:pathology* / Q000503:physiopathology*
D005353:Fibronectins; D010196:Pancreatic Elastase