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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1784.)
© 2006 American Heart Association, Inc.

Vascular Biology

Laminar Shear Stress Inhibits Cathepsin L Activity in Endothelial Cells

Manu O. Platt; Randall F. Ankeny; Hanjoong Jo

From the Coulter Department of Biomedical Engineering (M.O.P., R.F.A., H.J.), Georgia Institute of Technology, and the Division of Cardiology (H.J.), Emory University, Atlanta, Ga.

Correspondence to Hanjoong Jo, Department of Biomedical Engineering at Georgia Tech and Emory University, 308D WMB, Atlanta, GA 30322. E-mail hanjoong.jo{at}bme.gatech.edu

Objective— The cysteine proteases, cathepsins, have been implicated in vascular remodeling and atherosclerosis, processes known to be regulated by shear stress. It is not known, however, whether shear regulates cathepsins. We examined the hypothesis that shear stress regulates cathepsin activity in endothelial cells.

Methods and Results— Mouse aortic endothelial cells (MAECs) exposed to atheroprotective, unidirectional laminar shear (LS) degraded significantly less BODIPY-labeled elastin and gelatin in comparison to static and proatherogenic oscillatory shear (OS). The cathepsin inhibitor E64 also reduced this activity. Gelatin zymography showed that cathepsin activity of MAECs was blunted by LS exposure and by a cathepsin L inhibitor but not by cathepsin B and S inhibitors, whereas a cathepsin K inhibitor had a minor effect. Cathepsin L siRNA knocked down cathepsin L expression, gelatinase, and elastase activity in OS and static MAECs. A partial reduction of cathepsin B protein raised the possibility that the siRNA effect on the matrix protease activity could have been attributable to cathepsin L or B. Cathepsin B activity study using the synthetic peptide showed it was not regulated by shear.

Conclusions— These results suggest that cathepsin L is a shear-sensitive matrix protease and that it may play an important role in flow-mediated vascular remodeling and atherogenic responses.

Cathepsins have been implicated in vascular remodeling and atherosclerosis, but it is not known whether shear stress regulates them. Here, we show that atheroprotective laminar shear inhibits elastase and gelatinase activities in endothelial cells in a cathepsin L-dependent manner. This may protect vascular wall matrix integrity and prevent atherosclerosis.

Key Words: shear stress • cathepsin • elastase • gelatinase • atherosclerosis

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