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.

Cathepsin L Promotes Vascular Intimal Hyperplasia after Arterial Injury

“…Whole cell lysates were collected and protein concentrations determined by the micro bicinchoninic acid assay (Pierce), then 50 μl of Cysteine cathepsins B, L and S, which are endosomal and lysosomal proteases, participate in numerous physiological systems and are upregulated during inflammatory disorders and cancers. In humans, cathepsins can regulate apoptosis, major histocompatibility complex class II-dependent immune responses, antigen processing and extracellular matrix remodeling (22)(23)(24). Two distinct cathepsin L proteases are encoded by human cathepsin L gene, namely cathepsin L1 and cathepsin V (also known as cathepsin L2).…”

Possible Pivotal Role of Latent Chronic T. gondii Infection in the Pathogenesis of Atherosclerosis

“…Increased expression and translocation of lysosomal cathepsins contribute to macrophage apoptosis in atherogenesis [669] . Cathepsins of the cysteine protease family, such as CatB, C, H, F, K, L, O, S, V, W, and X/Z [671] function in terminal protein degradation optimally whithin acidic lysosomes [672] , and play an important role in development of atherosclerosis-based cardiovascular diseases [673][674][675][676][677][678] . Cathepsins are expressed in macrophages, endothelial and vascular smooth muscle cells (VSMCs) of atherosclerotic lesions [677] .…”

“…Lipoprotein modification and uptake by atherosclerotic lesion cells, mainly macrophages and VSMCs, are important pathological steps in the formation of atherosclerotic plaques [669,673,675,677,[680][681][682][683] . CatL [680,684,685] and CatB [686,687] expression is enhanced in human coronary atherosclerotic lesions, carotid lesions, and in abdominal aortic aneurysms [676] .…”

“…Macrophages, VSMCs, and endothelial cells can mobilize cathepsins also extracellularly, for example, the CatB, L, S, and K participated in plaque extracellular proteolysis [690] . The role of cysteine cathepsin proteases in lipid uptake, storage, and efflux has been partly elucidated [675,677] . Cathepsins have the capability to degrade LDL and reduce cholesterol efflux from macrophages, aggravating foam cell formation [677] .…”

“…The cathepsins translocated from lysosomes to cytosol or nuclei, caused foam cell apoptosis in the development and progression of atheroma [673] . In addition, lysosomal cell permeabilization due to exogenous reactive oxygen species may induce lysosomal leakage leading to release of cathepsins into the cytoplasm [675,692] . Cysteine cathepsins participated in the degradation of HDLs, thus reducing macrophage foam cell cholesterol efflux [675] .…”