Cathepsin cysteine proteases in cardiovascular disease

Department of Pathology , Maastricht University, Maestricht, Limburg, Netherlands
The FASEB Journal (Impact Factor: 5.04). 11/2007; 21(12):3029-41. DOI: 10.1096/fj.06-7924com
Source: PubMed


Extracellular matrix (ECM) remodeling is one of the underlying mechanisms in cardiovascular diseases. Cathepsin cysteine proteases have a central role in ECM remodeling and have been implicated in the development and progression of cardiovascular diseases. Cathepsins also show differential expression in various stages of atherosclerosis, and in vivo knockout studies revealed that deficiency of cathepsin K or S reduces atherosclerosis. Furthermore, cathepsins are involved in lipid metabolism. Cathepsins have the capability to degrade low-density lipoprotein and reduce cholesterol efflux from macrophages, aggravating foam cell formation. Although expression studies also demonstrated differential expression of cathepsins in cardiovascular diseases like aneurysm formation, neointima formation, and neovascularization, in vivo studies to define the exact role of cathepsins in these processes are lacking. Evaluation of the feasibility of cathepsins as a diagnostic tool revealed that serum levels of cathepsins L and S seem to be promising as biomarkers in the diagnosis of atherosclerosis, whereas cathepsin B shows potential as an imaging tool. Furthermore, cathepsin K and S inhibitors showed effectiveness in (pre) clinical evaluation for the treatment of osteoporosis and osteoarthritis, suggesting that cathepsin inhibitors may also have therapeutic effects for the treatment of atherosclerosis.

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Available from: Kitty Cleutjens, Apr 15, 2014
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    • "Among the cathepsin family members, cathepsin K has been shown to be one of the most potent mammalian collagenases in vivo and in vitro.11,13,14,15 Data from our group and others have shown that cathepsin K abounds in vascular cells (including smooth muscle cells and endothelial cells) and infiltrated macrophages of human and animal atherogenic lesions.3,16,17,18 The ablation of cathepsin K was shown to ameliorate obesity- and pressure overload-related cardiac dysfunction and remodeling.19,20 "
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    ABSTRACT: Purpose Cathepsin K is a potent collagenase implicated in human and animal atherosclerosis-based vascular remodeling. This study examined the hypothesis that serum CatK is associated with the prevalence of coronary artery disease (CAD). Materials and Methods Between January 2011 and December 2012, 256 consecutive subjects were enrolled from among patients who underwent coronary angiography and percutaneous coronary intervention treatment. A total of 129 age-matched subjects served as controls. Results The subjects' serum cathepsin K and high sensitive C-reactive protein (hs-CRP) and high-density lipoprotein cholesterol were measured. The patients with CAD had significantly higher serum cathepsin K levels compared to the controls (130.8±25.5 ng/mL vs. 86.9±25.5 ng/mL, p<0.001), and the patients with acute coronary syndrome had significantly higher serum cathepsin K levels compared to those with stable angina pectoris (137.1±26.9 ng/mL vs. 102.6±12.9 ng/mL, p<0.001). A linear regression analysis showed that overall, the cathepsin K levels were inversely correlated with the high-density lipoprotein levels (r=-0.29, p<0.01) and positively with hs-CRP levels (r=0.32, p<0.01). Multiple logistic regression analyses shows that cathepsin K levels were independent predictors of CAD (odds ratio, 1.76; 95% confidence interval, 1.12 to 1.56; p<0.01). Conclusion These data indicated that elevated levels of cathepsin K are closely associated with the presence of CAD and that circulating cathepsin K serves a useful biomarker for CAD.
    Full-text · Article · Jul 2014 · Yonsei Medical Journal
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    • "Cathepsin B has been well characterized for its role in protein degradations, which occurs either outside of the cell or in compartments within the cell (Bohley and Seglen, 1992). Studies in mammals have shown that cathepsin B plays various roles in maintaining normal cellular metabolism and the pathogenesis of many diseases including cancer (Mohamed and Sloane, 2006), inflammation (Lutgens et al., 2007), Alzheimer's disease (Haque et al., 2008) and cardiovascular diseases (Lutgens et al., 2007). Moreover, in vitro studies suggested that cathepsin B regulates major histocompatibility complex (MHC) class II-associated invariant chain (Ii) processing and antigen presentation. "
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    ABSTRACT: In teleost, cathepsin B has been identified from several species and shown to play roles in the host immune response during pathogen challenge. However, the mechanism of how cathepsin B modulates the immune response in teleosts remains poorly understood. In this study, we identified and characterized cathepsin B (LycCatB) and invariant chain (LycIi) from the large yellow croaker (Pseudosciaena crocea). Sequence comparison and phylogenetic analysis indicated that LycCatB and LycIi are highly conserved within teleosts. Quantitative RT-PCR analysis showed that LycCatB mRNA was widely expressed in all examined tissues. We then recombinantly expressed LycCatB and Lyc-TR-Ii (transmembrane domain removed Ii chain) in Pichia pastoris and E.coli, respectively. The recombinant LycCatB (rLycCatB) can hydrolyze the substrate Z-FR-AMC with a Km value of 40.68 μM. Furthermore, co-incubation of rLycCatB with rLyc-TR-Ii led to an efficient cleavage of rLyc-TR-Ii in a time-dependant manner. These results indicated that cathepsin B may be involved in MHC class II-associated Ii processing in large yellow croaker, and provide new information helping to elucidate the immunological functions of teleost cathepsin B.
    Full-text · Article · Apr 2014 · Developmental and comparative immunology
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    • "In addition to the AHRs and CYP1A, these populations appear to be highly differentiated at cathepsin F, cathepsin Z, CYP3A30, and the NADH ubiquinone oxidoreductase MLRQ subunit loci. Cathepsins are a large group of proteolytic enzymes that have been implicated in cardiomyopathies and cardiovascular disease, ultimately resulting in impaired pump function [55,56]. Given that the cardiovascular system is a main target of DLC toxicity in all vertebrates [48], it is reasonable to propose that alterations in the cathepsin coding sequence could contribute to existing differences in DLC sensitivity. "
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    ABSTRACT: The most toxic aromatic hydrocarbon pollutants are categorized as dioxin-like compounds (DLCs) to which extreme tolerance has evolved independently and contemporaneously in (at least) four populations of Atlantic killifish (Fundulus heteroclitus). Surprisingly, the magnitude and phenotype of DLC tolerance is similar among these killifish populations that have adapted to varied, but highly aromatic hydrocarbon-contaminated urban/industrialized estuaries of the US Atlantic coast. Multiple tolerant and neighboring sensitive killifish populations were compared with the expectation that genetic loci associated with DLC tolerance would be revealed. Since the aryl hydrocarbon receptor (AHR) pathway partly or fully mediates DLC toxicity in vertebrates, single nucleotide polymorphisms (SNPs) from 42 genes associated with the AHR pathway were identified to serve as targeted markers. Wild fish (N = 36/37) from four highly tolerant killifish populations and four nearby sensitive populations were genotyped using 59 SNP markers. Similar to other killifish population genetic analyses, strong genetic differentiation among populations was detected, consistent with isolation by distance models. When DLC-sensitive populations were pooled and compared to pooled DLC-tolerant populations, multi-locus analyses did not distinguish the two groups. However, pairwise comparisons of nearby tolerant and sensitive populations revealed high differentiation among sensitive and tolerant populations at these specific loci: AHR 1 and 2, cathepsin Z, the cytochrome P450s (CYP1A and 3A30), and the NADH dehydrogenase subunits. In addition, significant shifts in minor allele frequency were observed at AHR2 and CYP1A loci across most sensitive/tolerant pairs, but only AHR2 exhibited shifts in the same direction across all pairs. The observed differences in allelic composition at the AHR2 and CYP1A SNP loci were identified as significant among paired sensitive/tolerant populations of Atlantic killifish with multiple statistical tests. The genetic patterns reported here lend support to the argument that AHR2 and CYP1A play a role in the adaptive response to extreme DLC contamination. Additional functional assays are required to isolate the exact mechanism of DLC tolerance.
    Full-text · Article · Jan 2014 · BMC Evolutionary Biology
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