Cathepsins in heart disease–chewing on the heartache?

Blondelle, Jordan; Lange, Stephan; Greenberg, Barry; Cowling, Randy T.

doi:10.1152/ajpheart.00125.2015

Cited by 11 publications

(13 citation statements)

References 36 publications

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“…The role for cathepsin proteases in early heart and valve development is still not clearly defined, but analyzing cardiac systems in models of inherited disease can offer valuable insight into these processes ( 24 ). Here, we show that mutations in the gnptab gene, associated with the lysosomal disease MLII, alters the activity and localization of cysteine cathepsins and disrupts heart and AV valve development in zebrafish embryos.…”

Section: Discussionmentioning

confidence: 99%

“…Cathepsin proteases are lysosomal enzymes whose diverse functions range from protein turnover and hormone or neuropeptide processing to modulation of growth factor activation and stability ( 20 – 23 ). 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 ).…”

Section: Introductionmentioning

confidence: 99%

“…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 ). Although cathepsin proteases are known to be essential for tissue remodeling and can clearly perpetuate later-stage disease, their role during cardiovascular development remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…However, it has been reported that cathepsin B (CTSB) mediates the activation of the NLRP3 inflammasome. Increased cytoplasm levels of CTSB contribute to NLRP3 inflammasome activation, and CTSB suppression with a chemical inhibitor decreased the activation of the NLRP3 inflammasomes 29 , 30 . Moreover, the level of CTSB in the cytoplasm was associated with autophagic flux.…”

Section: Introductionmentioning

confidence: 99%

Taurine attenuates arsenic-induced pyroptosis and nonalcoholic steatohepatitis by inhibiting the autophagic-inflammasomal pathway

et al. 2018

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Arsenic exposure causes nonalcoholic steatohepatitis (NASH). Inflammation is a key contributor to the pathology of nonalcoholic fatty liver disease (NAFLD), including NASH. However, it is unclear how arsenic induces inflammation. In mouse livers, we show that arsenic trioxide (As2O3) induced NASH, increased autophagy and NLRP3 inflammasome activation, increased lipid accumulation, and resulted in dysregulation of lipid-related genes. Supplemented with taurine (Tau) attenuated the inflammation and autophagy caused by As2O3. In HepG2 cells, we found that As2O3-induced pyroptotic cell death was dependent upon the activation of NLRP3 inflammasome, which was CTSB-dependent. In addition, inhibiting autophagy alleviated the As2O3-induced increase of cytosolic CTSB expression and subsequent release of LDH, activation of the NLRP3 inflammasome, and pyroptosis. Moreover, we found that Tau alleviated As2O3-induced elevation of autophagy, CTSB expression, and activation of the NLRP3 inflammasome, and reduced the release of LDH, pyroptotic cell death, and inflammation. Interestingly, As2O3-induced lipid accumulation could not be alleviated by either inhibition of autophagy nor by inhibition of CTSB. Additionally, neither inhibition of the NLRP3 inflammasome or Tau treatment could alleviate lipid accumulation. These results demonstrated that As2O3-induced pyroptosis involves autophagy, CTSB, and the NLRP3 inflammasome cascade, and that Tau alleviates As2O3-induced liver inflammation by inhibiting the autophagic-CTSB-NLRP3 inflammasomal pathway rather than decreasing lipid accumulation. These findings give insight into the association of autophagy, inflammation, pyroptosis, and NASH induced by As2O3.

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“…Cathepsins have been associated with a variety of diseases such as rheumatoid arthritis [3], cancer [2], neurodegenerative disease [4], aneurysm formation [1], heart failure [5], and metabolic disturbances such as obesity [6], diabetes [7], and dyslipidemias [8].…”

Section: Introductionmentioning

confidence: 99%

Cathepsin B and S as markers for cardiovascular risk and all-cause mortality in patients with stable coronary heart disease during 10 years: a CLARICOR trial sub-study

et al. 2018

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Cathepsins in heart disease–chewing on the heartache?

Cited by 11 publications

References 36 publications

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

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

Taurine attenuates arsenic-induced pyroptosis and nonalcoholic steatohepatitis by inhibiting the autophagic-inflammasomal pathway

Cathepsin B and S as markers for cardiovascular risk and all-cause mortality in patients with stable coronary heart disease during 10 years: a CLARICOR trial sub-study

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