Signalling pathways linking cysteine cathepsins to adverse cardiac remodelling

O'Toole, Dylan; Zaeri, Ali; Nicklin, Stuart A.; French, Anne; Loughrey, Christopher M.; Martin, Tamara P.

doi:10.1016/j.cellsig.2020.109770

Cited by 8 publications

(5 citation statements)

References 168 publications

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“…No less important, the strong independent correlation found with the left ventricle end-diastolic volume merits further examination as it suggests a biological involvement of CatK also in the cardiac morpho-functional adaptations which characterize renal patients. Such a hypothesis would pair well with recent studies demonstrating a direct role of cysteine proteases in pathological cardiac remodelling, particularly in chronic heart failure [26,27].…”

Section: Discussionsupporting

confidence: 75%

Decreased Cathepsin-K Mirrors the Severity of Subclinical Atherosclerosis in Kidney Transplant Recipients

Bolignano¹,

Greco²,

Arcidiacono³

et al. 2022

Rev. Cardiovasc. Med.

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Background: In kidney transplantation (Ktx) recipients, cardiovascular (CV) disease remains the leading cause of death. Abnormal carotid intima-media thickness (IMT) represents a valid indicator of incipient atherosclerosis also in this setting. Cathepsin-K (CatK) is a cysteine protease involved in vascular remodelling, as well as in progressive atherosclerosis. In this study we evaluated clinical predictors of CatK in Ktx recipients, with a particular focus on its possible relationships with subclinical atherosclerosis. Methods: Circulating CatK was measured in 40 stable Ktx recipients together with several laboratory, clinical and echocardiography parameters. 30 healthy subjects and 30 hemodialysis (HD) patients served as controls for CatK values. Carotid IMT was measured in Ktx and these subjects were then categorized according to age-gender reference cut-offs of normal IMT. Results: CatK levels were similar in Ktx recipients and healthy subjects but significantly reduced as compared to HD (p = 0.0001). In Ktx, at multivariate analyses CatK was associated with the LV end-diastolic volume (LVEDVi) (β = 0.514; p = 0.05), Ktx vintage (β = -0.333; p = 0.05) and mean IMT (β = -0.545; p = 0.05); this latter robust inverse association was confirmed also in another multivariate model with IMT as the dependent variable. Logistic regression analyses confirmed the beneficial meaning of CatK increase towards subclinical atherosclerosis [Odds Ratio (OR) 0.761; 95% Confidence Interval (CI) 0.569-0.918, p = 0.04]. At Receiver Operating Characteristics (ROC) analyses, CatK held a remarkable discriminatory power in identifying Ktx patients with abnormally increased IMT [Area Under the Curve (AUC) 0.763; 95% CI 0.601-0.926; p = 0.001]). Conclusions: In Ktx recipients, reduced CatK levels reflect the time-dependent improvement in the uremic milieu, cardiac adaptations and, above all, the severity of subclinical atherosclerosis. CatK measurement in Ktx may therefore hold significance for improving early CV risk stratification.Keywords: kidney transplantation; Cathepsin-K; carotid intima-media thickness; subclinical atherosclerosis Recently, we reported increased CatK levels among chronic HD patients which reflected an altered bone mineral metabolism, also holding prognostic value for CV mortality [13,14]. To the best of our knowledge, however, no study has analysed so far such protease in the context of Ktx, particularly in relationship with the presence of early, asymptomatic CV disease.

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Section: Discussionsupporting

confidence: 75%

Decreased Cathepsin-K Mirrors the Severity of Subclinical Atherosclerosis in Kidney Transplant Recipients

Bolignano¹,

Greco²,

Arcidiacono³

et al. 2022

Rev. Cardiovasc. Med.

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“… 30–33 However, the role that cathepsin L plays in cardiomyocyte apoptosis is less clear. 33–36 We demonstrate that in the context of reperfusion injury CAA0225 completely normalized the increase in diastolic calcium handling post-reperfusion and led to a substantial reduction in apoptosis as measured using TUNEL staining, caspase 3/7 activity and PARP-1 cleavage. These data provide mechanistic insight regarding how targeting cathepsin-L reduces infarct size and improves cardiac function in ex vivo hearts post-reperfusion injury.…”

Section: Discussionmentioning

confidence: 69%

Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size

McCarroll

Nather

et al. 2021

Cardiovascular Research

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Aims Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevated myocardial infarction (STEMI) to heart failure. Here we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury. Methods and Results We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 hour post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies, demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis. Conclusion Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI. Translational perspective New therapeutic targets are urgently required to limit myocardial damage after reperfusion injury. We identified cardiac release of the protease cathepsin-L among patients following primary percutaneous coronary intervention (PPCI). Elevated serum levels of cathepsin-L were associated with reduced contractile function and increased infarct size at 24 hour and 6 months post-PPCI. Work conducted using animal models indicated that cardiac release of cathepsin-L mediated cardiac dysfunction following reperfusion injury. Specific inhibition of cathepsin-L prevented abnormal calcium handling, reduced infarct size and improved contractile function. These novel findings offer the prospect of targeting cathepsin-L-mediated cardiac dysfunction after PPCI.

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“…The most abundant proteases that are stored in lysosomal compartments are cathepsins which play a vital role in protein degradation, immune responses, and cell death processes (Yadati et al 2020 ; Conus and Simon 2008 ). Cathepsins are categorized into three groups based on the type of amino acid at the active site: serine cathepsins (cathepsin A and G), aspartic cathepsins (cathepsin D and E) and cysteine cathepsins (cathepsin B, C, F, H, K, L, O, S, V, X, and W) (Yadati et al 2020 ; Liu et al 2018 ; O'Toole et al 2020 ). In our previous study, He et al (He et al 2022 ) demonstrate that inhibition of a specific member of cathepsin (cathepsin-L) leads to improved cardiac function and reduced infarct size in an ex vivo rat model of myocardial ischemia/reperfusion injury.…”

Section: Resultsmentioning

confidence: 99%

Pharmacological inhibition of RUNX1 reduces infarct size after acute myocardial infarction in rats and underlying mechanism revealed by proteomics implicates repressed cathepsin levels

Chen,

Wang,

Zhang

et al. 2024

Funct Integr Genomics

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Myocardial infarction (MI) results in prolonged ischemia and the subsequent cell death leads to heart failure which is linked to increased deaths or hospitalizations. New therapeutic targets are urgently needed to prevent cell death and reduce infarct size among patients with MI. Runt-related transcription factor-1 (RUNX1) is a master-regulator transcription factor intensively studied in the hematopoietic field. Recent evidence showed that RUNX1 has a critical role in cardiomyocytes post-MI. The increased RUNX1 expression in the border zone of the infarct heart contributes to decreased cardiac contractile function and can be therapeutically targeted to protect against adverse cardiac remodelling. This study sought to investigate whether pharmacological inhibition of RUNX1 function has an impact on infarct size following MI. In this work we demonstrate that inhibiting RUNX1 with a small molecule inhibitor (Ro5-3335) reduces infarct size in an in vivo rat model of acute MI. Proteomics study using data-independent acquisition method identified increased cathepsin levels in the border zone myocardium following MI, whereas heart samples treated by RUNX1 inhibitor present decreased cathepsin levels. Cathepsins are lysosomal proteases which have been shown to orchestrate multiple cell death pathways. Our data illustrate that inhibition of RUNX1 leads to reduced infarct size which is associated with the suppression of cathepsin expression. This study demonstrates that pharmacologically antagonizing RUNX1 reduces infarct size in a rat model of acute MI and unveils a link between RUNX1 and cathepsin-mediated cell death, suggesting that RUNX1 is a novel therapeutic target that could be exploited clinically to limit infarct size after an acute MI.

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Signalling pathways linking cysteine cathepsins to adverse cardiac remodelling

Cited by 8 publications

References 168 publications

Decreased Cathepsin-K Mirrors the Severity of Subclinical Atherosclerosis in Kidney Transplant Recipients

Decreased Cathepsin-K Mirrors the Severity of Subclinical Atherosclerosis in Kidney Transplant Recipients

Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size

Pharmacological inhibition of RUNX1 reduces infarct size after acute myocardial infarction in rats and underlying mechanism revealed by proteomics implicates repressed cathepsin levels

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