This Article Full Text Full Text (PDF) All Versions of this Article: 26/8/1784    most recent 01.ATV.0000227470.72109.2bv1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Platt, M. O. Articles by Jo, H. Search for Related Content PubMed PubMed Citation Articles by Platt, M. O. Articles by Jo, H. Pubmed/NCBI databases Substance via MeSH

(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

This article has been cited by other articles:

				C.-J. Chang, C.-C. Chen, L.-A. Hsu, G.-J. Chang, Y.-H. Ko, C.-F. Chen, M.-Y. Chen, S.-H. Yang, and J.-H. S. Pang Degradation of the Internal Elastic Laminae in Vein Grafts of Rats with Aortocaval Fistulae: Potential Impact on Graft Vasculopathy Am. J. Pathol., May 1, 2009; 174(5): 1837 - 1846. [Abstract] [Full Text] [PDF]

				K. Balachandran, P. Sucosky, H. Jo, and A. P. Yoganathan Elevated cyclic stretch alters matrix remodeling in aortic valve cusps: implications for degenerative aortic valve disease Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H756 - H764. [Abstract] [Full Text] [PDF]

				G. P. Kwon, J. L. Schroeder, M. J. Amar, A. T. Remaley, and R. S. Balaban Contribution of Macromolecular Structure to the Retention of Low-Density Lipoprotein at Arterial Branch Points Circulation, June 3, 2008; 117(22): 2919 - 2927. [Abstract] [Full Text] [PDF]

				S. P. M. Lutgens, K. B. J. M. Cleutjens, M. J. A. P. Daemen, and S. Heeneman Cathepsin cysteine proteases in cardiovascular disease FASEB J, October 1, 2007; 21(12): 3029 - 3041. [Abstract] [Full Text] [PDF]

				S. L. Tressel, R.-P. Huang, N. Tomsen, and H. Jo Laminar Shear Inhibits Tubule Formation and Migration of Endothelial Cells by an Angiopoietin-2-Dependent Mechanism Arterioscler Thromb Vasc Biol, October 1, 2007; 27(10): 2150 - 2156. [Abstract] [Full Text] [PDF]

				Y. S. Chatzizisis, A. U. Coskun, M. Jonas, E. R. Edelman, C. L. Feldman, and P. H. Stone Role of Endothelial Shear Stress in the Natural History of Coronary Atherosclerosis and Vascular Remodeling: Molecular, Cellular, and Vascular Behavior J. Am. Coll. Cardiol., June 26, 2007; 49(25): 2379 - 2393. [Abstract] [Full Text] [PDF]

				M. O. Platt, R. F. Ankeny, G.-P. Shi, D. Weiss, J. D. Vega, W. R. Taylor, and H. Jo Expression of cathepsin K is regulated by shear stress in cultured endothelial cells and is increased in endothelium in human atherosclerosis Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1479 - H1486. [Abstract] [Full Text] [PDF]