Cysteinyl cathepsins in cardiovascular diseases

Zhang, Xian; Luo, Songyuan; Wang, Minjie; Shi, Guo‐Ping

doi:10.1016/j.bbapap.2020.140360

Cited by 26 publications

(15 citation statements)

References 219 publications

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“…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]. Furthermore, CTSB was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease [18].…”

Section: Cathepsin Involvement In the Pathophysiology Of Mucopolysaccmentioning

confidence: 99%

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

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Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

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Section: Cathepsin Involvement In the Pathophysiology Of Mucopolysaccmentioning

confidence: 99%

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

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“…Several cathepsin proteases, namely B, K, L, and S, have been implicated in onset of a variety of cardiovascular diseases ( 24 – 26 ). Increased expression of cathepsins K, L, and S is associated with atherosclerosis, cardiac hypertrophy, and valvular stenosis ( 7 , 27 – 29 ), with several studies suggesting cathepsin deficiency protects against these forms of cardiac dysfunction ( 30 , 31 ). A role for cathepsins K and L has also been shown during heart regeneration and valvular remodeling ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation

Lu¹,

Moreland²,

Christian³

et al. 2020

JCI Insight

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Although congenital heart defects (CHDs) represent the most common birth defect, a comprehensive understanding of disease etiology remains unknown. This is further complicated since CHDs can occur in isolation or as a feature of another disorder. Analyzing disorders with associated CHDs provides a powerful platform to identify primary pathogenic mechanisms driving disease. Aberrant localization and expression of cathepsin proteases can perpetuate later-stage heart diseases, but their contribution toward CHDs is unclear. To investigate the contribution of cathepsins during cardiovascular development and congenital disease, we analyzed the pathogenesis of cardiac defects in zebrafish models of the lysosomal storage disorder mucolipidosis II (MLII). MLII is caused by mutations in the GlcNAc-1-phosphotransferase enzyme (Gnptab) that disrupt carbohydrate-dependent sorting of lysosomal enzymes. Without Gnptab, lysosomal hydrolases, including cathepsin proteases, are inappropriately secreted. Analyses of heart development in gnptab -deficient zebrafish show cathepsin K secretion increases its activity, disrupts TGF-β–related signaling, and alters myocardial and valvular formation. Importantly, cathepsin K inhibition restored normal heart and valve development in MLII embryos. Collectively, these data identify mislocalized cathepsin K as an initiator of cardiac disease in this lysosomal disorder and establish cathepsin inhibition as a viable therapeutic strategy.

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“…Accordingly, CatD is considered an essential regulator of cell signaling and cellular homeostasis [ 31 ]. Dysregulated CatD activity plays an important role in diseases such as acute kidney injury, coronary events, neurodegenerative diseases, and cancer (reviewed in [ 31 , 32 , 33 , 34 ]).…”

Section: Lysosomal Peptidasesmentioning

confidence: 99%

Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

et al. 2022

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Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and pathologies, either within lysosomes, upon secretion into the cell cytoplasm or extracellular space, or bound to the plasma membrane. In cancer, lysosomal peptidases are generally associated with disease progression, as they participate in crucial processes leading to changes in cell morphology, signaling, migration, and invasion, and finally metastasis. However, they can also enhance the mechanisms resulting in cancer regression, such as apoptosis of tumor cells or antitumor immune responses. Lysosomal peptidases have also been identified as hallmarks of aging and neurodegeneration, playing roles in oxidative stress, mitochondrial dysfunction, abnormal intercellular communication, dysregulated trafficking, and the deposition of protein aggregates in neuronal cells. Furthermore, deficiencies in lysosomal peptidases may result in other pathological states, such as lysosomal storage disease. The aim of this review was to highlight the role of lysosomal peptidases in particular pathological processes of cancer and neurodegeneration and to address the potential of lysosomal peptidases in diagnosing and treating patients.

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Cysteinyl cathepsins in cardiovascular diseases

Cited by 26 publications

References 219 publications

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation

Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

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