Cysteine protease cathepsins in cardiovascular disease: from basic research to clinical trials

Abstract

Cysteine protease cathepsins have traditionally been considered as lysosome-restricted proteases that mediate proteolysis of unwanted proteins. However, studies from the past decade demonstrate that these proteases are localized not only in acidic compartments (endosomes and lysosomes), where they participate in intracellular protein degradation, but also in the extracellular milieu, plasma membrane, cytosol, nucleus, and nuclear membrane, where they mediate extracellular matrix protein degradation, cell signalling, and protein processing and trafficking through the plasma and nuclear membranes and between intracellular organelles. Studies in experimental disease models and on cathepsin-selective inhibitors, as well as plasma and tissue biomarker data from animal models and humans, have verified the participation of cysteinyl cathepsins in the pathogenesis of many cardiovascular diseases, including atherosclerosis, myocardial infarction, cardiac hypertrophy, cardiomyopathy, abdominal aortic aneurysms, and hypertension. Clinical trials of cathepsin inhibitors in chronic inflammatory diseases suggest the utility of these inhibitors for the treatment of cardiovascular diseases and associated complications. Moreover, development of cell transfer technologies that enable ex vivo cell treatment with cathepsin inhibitors might limit the unwanted systemic effects of cathepsin inhibition and provide new avenues for targeting cysteinyl cathepsins. In this Review, we summarize the available evidence implicating cysteinyl cathepsins in the pathogenesis of cardiovascular diseases, discuss their potential as biomarkers of disease progression, and explore the potential of cathepsin inhibitors for the treatment of cardiovascular diseases.

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…A variety of evidence demonstrate that abnormal expression and/or activity of both lysosomal and extra-lysosomal CTSs correlate with MPS major clinical manifestations such as neuropathology, bone and joint defects, and cardiovascular disorders ( Table 3). [168] In particular, the cysteine CTSB, involved in the degradation of collagen [176] and responsible for heart dilatation [19], displayed a marked increase of its activity in MPS I mouse model, suggesting that the progressive heart failure and valve disease observed in these mice may be dependent on CTSB overexpression [160]. The in vivo treatment of MPS I mice with a CTSB inhibitor reduced aortic dilatation and heart valve thickening, and led to an improvement of cardiac function, suggesting that CTSB inhibition may have a potential benefit in the disease [161].…”

“…Indeed, cardiac disease has been described in MPS III patients as well as in patients affected by the other MPS subtypes [178,179]. Multiple evidence demonstrated the involvement of CTSs in many cardiovascular diseases, including atherosclerosis, cardiac hypertrophy, cardiomyopathy, myocardial infarction, and hypertension, some of which are common clinical manifestations in MPSs [8,10,[17][18][19]36,56,61,66,76,80,81]. In particular, CTSB results in being up-regulated in cardiomyocytes in response to hypertrophic stimuli both in vivo and in vitro [180].…”

“…A specific CTSB inhibitor, namely CA-074Me, reduced cardiac dysfunction, remodeling, and fibrosis in a rat model of myocardial infarction [181]. Studies aimed to explore the potential of CTS inhibitors for the treatment of cardiovascular diseases are ongoing [19], and targeting CTSs-based therapy might provide new avenues for the treatment of MPSs as well.…”

Deficiency of immunoglobulin E protects mice from experimental abdominal aortic aneurysms

“…For example, IL6 and MAPK signaling stimulate MMP and cysteinyl cathepsin expression in macrophages and fibroblasts . Both MMPs and cysteinyl cathepsins play essential roles in AAA development . Although not tested in this study, reduced numbers of CD31 + microvessel contents in AAA lesions from Apoe −/− Ige −/− mice (Figures G and G) suggest impaired protease expression and extracellular matrix degradation.…”

Online Databases and Non-coding RNAs in Cardiovascular Diseases

“…However, the basic research on cardiovascular disease was still limited [1,2]. In-depth basic research could provide a guiding direction for new methods in treating cardiovascular diseases [3]. Therefore, exploring the molecular and cellular mechanisms in the pathogenesis of cardiovascular disease could help us understand the disease process, discover new biomarkers, and find new therapeutic targets [4,5].…”