Effects of Mast Cell Chymase on Cardiac Fibroblast Function

Abstract

Mast cells are bone marrow‐derived effector cells that have been described historically for their role in mediating allergic reactions. More recently, they have received considerable attention due to their involvement in innate defense, tissue remodeling and other processes. Several studies have illustrated roles for mast cells in cardiovascular diseases including ventricular remodeling associated with myocardial infarction, hypertension and volume overload. Mast cells produce a variety of secretory components including cytokines, proteases, growth factors and fatty acid metabolites. The compliment of components synthesized by a given mast cell appears to be dictated by the tissue microenvironment giving these cells diverse roles in tissue homeostasis and disease. Mast cell proteases including tryptase and chymase are some of the most abundant proteins produced by mast cells. Several studies have illustrated that mast cell chymase plays a significant role in the formation of angiotensin II in the heart and thus this protease may indirectly promote a fibrotic response via angiotensin II‐induced TGF‐beta production. However, the direct effect of this protease on cardiac fibroblast function has not been evaluated. The present studies were performed to elucidate the effects of chymase on isolated cardiac fibroblasts. Fibroblasts were treated for 24 hours with varying doses of chymase (0 to 1000 ng/ml) and the effects on proliferation, collagen scaffold remodeling, myofibroblast formation and expression of extracellular matrix components assayed. Treatment of cardiac fibroblasts with chymase significantly reduced the conversion of quiescent fibroblasts to a myofibroblast phenotype. Chymase also impaired contraction of three‐dimensional collagen gels and the expression of specific extracellular matrix components by fibroblasts. These studies illustrate that treatment of isolated cardiac fibroblasts with mast cell chymase elicits an anti‐fibrotic effect, which may contribute to the transition to heart failure in vivo.