Cysteinyl cathepsins and mast cell proteases in the pathogenesis and therapeutics of cardiovascular diseases

Abstract

The initiation and progression of cardiovascular diseases involve extensive arterial wall matrix protein degradation. Proteases are essential to these pathological events. Recent discoveries suggest that proteases do more than catabolize matrix proteins. During the pathogenesis of atherosclerosis, abdominal aortic aneuryms, and associated complications, cysteinyl cathepsins and mast cell tryptases and chymases participate importantly in vascular cell apoptosis, foam cell formation, matrix protein gene expression, and pro-enzyme, latent cytokine, chemokine, and growth factor activation. Experimental animal disease models have been invaluable in examining each of these protease functions. Deficiency and pharmacological inhibition of cathepsins or mast cell proteases have allowed their in vivo evaluation in the setting of pathological conditions. Recent discoveries of highly selective and potent inhibitors of cathepsins, chymase, and tryptase, and their applications in vascular diseases in animal models and non-vascular diseases in human trials, have led to the hypothesis that selective inhibition of cathepsins, chymases, and tryptase will benefit patients suffering from cardiovascular diseases. This review highlights recent discoveries from in vitro cell-based studies to experimental animal cardiovascular disease models, from protease knockout mice to treatments with recently developed selective and potent protease inhibitors, and from patients with cathepsin-associated non-vascular diseases to those affected by cardiovascular complications.

Figure 1

Illustration of cysteinyl cathepsin functions in the pathogenesis of vascular diseases, such as atherosclerosis and abdominal aortic aneurysm. Cathepsins can originate from inflammatory cells or from vascular SMCs and ECs under inflammatory conditions.

Figure 2

Chemical structures of the broad cathepsin inhibitors E64d (A) and JPM-ethyl ester (B), and of the CatS-selective inhibitors K11777 (C) and LHVS (D).

Figure 3

Illustration of mast cell protease functions in the pathogenesis of atherosclerosis and abdominal aortic aneurysm.