Proteolytic remodeling of elastin and collagen in the arterial wall contribute to atheroscleroticinitiation and progress. Cysteine cathepsins are powerful elastases and collagenases, and have been implicatedunder biochemical and biomechanical stimuli that lead to plaque progression. Cathepsins K, L, and S areupregulated in endothelial cells subject to disturbed blood flow, where plaques preferentially develop.Pharmaceutical companies have developed cathepsin inhibitors and a number have entered clinical trials, withsome ending early due to off target effects.1 Cathepsin expression and activity are regulated by endogenousprotein inhibitors as well as proteolytic interactive networks that are not completely understood. Through in vitrostudies, we have recently shown that cathepsin levels are subject to cathepsin-on-cathepsin cleavage, or cathepsincannibalism. This has unexpected implications for protease cross-reactivity with pharmaceutical inhibitors, andmay explain the observed off target effects. To better understand the complex system of proteolytic regulation,and improve the design of treatments aimed at decreasing cathepsin mediated arterial remodeling, we haveconstructed and validated a computational model of cathepsins K and S activity towards elastin, collagen, andeach other to simulate the effects on matrix degradation following treatment with protease inhibitors of cellsduring atherosclerosis.
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