Mast Cell Chymase Induces Smooth Muscle Cell Apoptosis by a Mechanism Involving Fibronectin Degradation and Disruption of Focal Adhesions

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 23; no. 2; pp. 238 - 243
• Main Authors: Leskinen, Markus J, Lindstedt, Ken A, Wang, Yenfeng, Kovanen, Petri T
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.02.2003; Hagerstown, MD Lippincott
• Subjects: Animals; Aorta - cytology; Apoptosis - physiology; Biological and medical sciences; Blood vessels and receptors; Cell Survival - physiology; Cells, Cultured; Chymases; Fibronectins - metabolism; Focal Adhesions - metabolism; Fundamental and applied biological sciences. Psychology; Male; Mast Cells - enzymology; Mast Cells - physiology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - physiology; Rats; Rats, Wistar; Serine Endopeptidases - physiology; Signal Transduction - physiology; Vertebrates: cardiovascular system; smooth muscle cell; Serine endopeptidases; Enzyme; Biological activity; Fibronectin; Chymase; Myocyte; Degradation; Peptidases; Enzymatic activity; focal adhesion kinase; Blood vessel; Hydrolases; Extracellular matrix; Mast cell; Circulatory system; Vascular wall; Apoptosis
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000051405.68811.4D

OBJECTIVE—Chymase released from activated mast cells has been shown to induce apoptosis of vascular smooth muscle cells (SMCs) in vitro. The proteolytic activity of chymase is essential for the proapoptotic effect, but the mechanism of chymase-induced apoptosis has remained unknown. METHODS AND RESULTS—Here we show by means of FACS analysis, immunohistochemistry, and Western blotting that mast cell–derived chymase induces SMC apoptosis by a mechanism involving degradation of an extracellular matrix component, fibronectin (FN), with subsequent disruption of focal adhesions. The FN degradation products induced SMC apoptosis of similar magnitude and with similar changes in outside-in signaling, as did chymase. Sodium orthovanadate, an inhibitor of tyrosine phosphatases, inhibited the chymase-induced SMC apoptosis. Focal adhesion kinase (FAK), one of the key mediators of integrin–extracellular matrix interactions and cell survival, was rapidly degraded in the presence of chymase or FN degradation products. Loss of phosphorylated FAK (p-FAK) resulted in a rapid dephosphorylation of the p-FAK–dependent downstream mediator Akt. CONCLUSIONS—The results suggest that chymase-secreting mast cells can mediate apoptosis of neighboring SMCs through a mechanism involving degradation of pericellular FN and disruption of the p-FAK–dependent cell-survival signaling cascade.