Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In atherosclerosis, accumulation of cholesterol in macrophages may partially depend on its defective removal by high-density lipoproteins (HDL). We studied the proteolytic effect of cathepsins F, S, and K on HDL(3) and on lipid-free apoA-I, and its consequence on their function as inductors of cholesterol efflux from cholesterol-filled mouse peritoneal macrophages in vitro. Incubation of HDL(3) with cathepsin F or S, but not with cathepsin K, led to rapid loss of prebeta-HDL, and reduced cholesterol efflux by 50% in only 1min. Cathepsins F or K partially degraded lipid-free apoA-I and reduced its ability to induce cholesterol efflux, whereas cathepsin S totally degraded apoA-I, leading to complete loss of apoA-I cholesterol acceptor function. These results suggest that cathepsin-secreting cells induce rapid depletion of lipid-poor (prebeta-HDL) and lipid-free apoA-I and inhibit cellular cholesterol efflux, so tending to promote the formation and maintenance of foam cells in atherosclerotic lesions.
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PMID:Cathepsins F and S block HDL3-induced cholesterol efflux from macrophage foam cells. 1465 73

Cathepsins, the lysosomal cysteine proteases, are involved in vascular remodeling and atherosclerosis. Genetic knockout of cathepsins S and K in mice has shown to reduce atherosclerosis, although the molecular mechanisms remain unclear. Because atherosclerosis preferentially occurs in arteries exposed to disturbed flow conditions, we hypothesized that shear stress would regulate cathepsin K expression and activity in endothelial cells. Mouse aortic endothelial cells (MAEC) exposed to proatherogenic oscillatory shear (OS, +/- 5 dyn/cm(2) for 1 day) showed significantly higher cathepsin K expression and activity than that of atheroprotective, unidirectional laminar shear stress (LS, 15 dyn/cm(2) for 1 day). Western blot and active-site labeling studies showed an active, mature form of cathepsin K in the conditioned medium of MAEC exposed to OS but not in that of LS. Functionally, MAEC exposed to OS significantly increased elastase and gelatinase activity above that of LS. The OS-dependent elastase and gelatinase activities were significantly reduced by knocking down cathepsin K with small-interfering (si) RNA, but not by a nonsilencing siRNA control, suggesting that cathepsin K is a shear-sensitive protease. In addition, immunohistochemical analysis of atherosclerotic human coronary arteries showed a positive correlation between the cathepsin K expression levels in endothelium and elastic lamina integrity. These findings suggest that cathepsin K is a mechanosensitive, extracellular matrix protease that, in turn, may be involved in arterial wall remodeling and atherosclerosis.
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PMID:Expression of cathepsin K is regulated by shear stress in cultured endothelial cells and is increased in endothelium in human atherosclerosis. 1709 27

Proteolytic degradation of elastic fibers is associated with a broad spectrum of pathological conditions such as atherosclerosis and pulmonary emphysema. We have studied the interaction between elastins and human cysteine cathepsins K, L, and S, which are known to participate in elastinolytic activity in vivo. The enzymes showed distinctive preferences in degrading elastins from bovine neck ligament, aorta, and lung. Different susceptibility of these elastins to proteolysis was attributed to morphological differences observed by scanning electron microscopy. Kinetics of cathepsin binding to the insoluble substrate showed that the process occurs in two steps. The enzyme is initially adsorbed on the elastin surface in a nonproductive manner and then rearranges to form a catalytically competent complex. In contrast, soluble elastin is bound directly in a catalytically productive manner. Studies of enzyme partitioning between the phases showed that cathepsin K favors adsorption on elastin; cathepsin L prefers the aqueous environment, and cathepsin S is equally distributed among both phases. Our results suggest that elastinolysis by cysteine cathepsins proceeds in cycles of enzyme adsorption, binding of a susceptible peptide moiety, hydrolysis, and desorption. Alternatively, the enzyme may also form a new catalytic complex without prior desorption and re-adsorption. In both cases the active center of the enzymes remains at least partly accessible to inhibitors. Elastinolytic activity was readily abolished by cystatins, indicating that, unlike enzymes such as leukocyte elastase, pathological elastinolytic cysteine cathepsins might represent less problematic drug targets. In contrast, thyropins were relatively inefficient in preventing elastinolysis by cysteine cathepsins.
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PMID:Interaction between human cathepsins K, L, and S and elastins: mechanism of elastinolysis and inhibition by macromolecular inhibitors. 1722 55

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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PMID:Cathepsin cysteine proteases in cardiovascular disease. 1752 80

Cathepsin K, a potent extracellular matrix degrading cysteine protease, has been linked to the pathogenesis of osteoporosis, arthritis, cardiovascular and respiratory diseases. Here, we report the effects of cathepsin K deficiency (ctsK-/-) on atherosclerotic plaque formation in brachiocephalic arteries in an aggressive atherosclerosis model using apoE-deficient mice on cholate-containing high fat diet (HFD). On this diet, apoE-/- mice displayed severe lesions with buried fibrous caps after 8 weeks, whereas the apoE-/-ctsK-/- mice revealed a significantly decreased number of buried fibrous caps accompanied by increased collagen content in plaque areas and fibrous cap thickness. After 16 weeks of HFD, ctsK-/- mice had smaller plaque areas and maintained the structure of the tunica media in terms of their smooth muscle cell content and elastic lamina integrity. Overall macrophage content in the tunica media was lower in ctsK-/- mice but higher in the plaque area after 8 weeks of HFD. Decreased apoptosis rates in atherosclerotic plaques in brachiocephalic arteries of cathepsin K-deficient indicated a lower level of inflammation. In conclusion, cathepsin K deficiency appears to increase lesion stability in brachiocephalic arteries by maintaining the integrity of the tunica media and by decreasing plaque vulnerability to rupture.
Atherosclerosis 2008 Sep
PMID:Role of cathepsin K in structural changes in brachiocephalic artery during progression of atherosclerosis in apoE-deficient mice. 1829 3

Cystatin C and cathepsins could play a role in almost all processes involved in atherosclerotic lesion formation by their degradation of extracellular matrix proteins and apolipoprotein B100, the protein moiety of LDL. Several cysteine cathepsins are upregulated in human lesions accompanied by a decrease in cystatin C, the major inhibitor of cysteine cathepsins. Recent research show that atherosclerotic mice deficient in cystatin C display increased elastic lamina degradation as well as larger plaque formation. Cathepsin S- and K-deficient atherosclerotic mice, on the other hand, both have less atherosclerosis, where cathepsin S-/- mice exhibited fewer plaque ruptures and cathepsin K-/- larger foam cells than control mice. This article reviews possible roles of cystatin C and cathepsins in different processes and stages of the atherosclerotic disease.
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PMID:Cystatin C and cathepsins in cardiovascular disease. 1850 21

Cathepsin K is a highly potent collagenase and the predominant papain-like cysteine protease expressed in osteoclasts. Cathepsin K deficiencies in humans and mice have underlined the central role of this protease in bone resorption and, thus, have rendered the enzyme as an attractive target for anti-resorptive osteoporosis therapy. In the past decade, a lot of efforts have been made in developing highly potent, selective and orally applicable cathepsin K inhibitors. Some of these inhibitors have passed preclinical studies and are presently in clinical trials at different stages of advancement. The development of the inhibitors and preliminary results of the clinical trials revealed problems and lessons concerning the in situ specificity of the compounds and their tissue targeting. In this review, we briefly summarize the history of cathepsin K research and discuss the current development of cathepsin K inhibitors as novel anti-resorptives for the treatment of osteoporosis. We also discuss potential off-target effects of cathepsin K inhibition and alternative applications of cathepsin K inhibitors in arthritis, atherosclerosis, blood pressure regulation, obesity and cancer.
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PMID:Cathepsin K inhibitors for osteoporosis and potential off-target effects. 1938 76

Cathepsin K (catK), a lysosomal cysteine protease, exerts strong elastinolytic and collagenolytic activity and is implicated in a range of pathological disorders including cardiovascular disease. CatK expression was found to be elevated in human aortic aneurysm pointing to a role in this vasculopathy. In the angiotensin II (Ang II)-induced mouse model for aneurysm formation, catK, S and C expression was strongly upregulated. Therefore, we investigated the effect of catK deficiency on Ang II-induced aneurysm formation in the abdominal aorta of apoE-/- mice. Contrary to our expectations, catK deficiency did not protect against aneurysm formation, nor did it affect medial elastin breaks. Proteolytic activity in abdominal aortic lysates were comparable between apoE-/- and catK-//-apoE-/- mice. Adventitial presence of catS- and catC-expressing cells was significantly increased in catK-/-//apoE-/- versus apoE-/- mice, which might have compensated for the deficiency of catK-derived proteolysis in the aneurysm tissue of catK deficient apoE-/- mice. Circulating granulocytes and activated T cell numbers were significantly increased in Ang II-infused catK-/-//apoE-/- mice, which is consistent with the borderline significant increase in adventitial leukocyte content in catK-/-//apoE-/- compared to apoE-/- mice. Strikingly, despite unchanged proteolytic activity in AAA lesions, collagen content in the aneurysm was significantly increased in catK-//-apoE-/- mice. In conclusion, while catK deficiency has major impact on various vasculopathies, it did not affect murine aneurysm formation.
Atherosclerosis 2010 Mar
PMID:Cathepsin K gene disruption does not affect murine aneurysm formation. 1977 91

Cathepsin K, the most potent mammalian collagenase, has been implicated in osteoporosis, cancer metastasis, atherosclerosis, and arthritis. Although procathepsin K is stable and readily detected, the active mature cathepsin K eludes detection by in vitro methods due to its shorter half-life and inactivation at neutral pH. We describe, for the first time, reliable detection, visualization, and quantification of mature cathepsin K to femtomole resolution using gelatin zymography. The specificity of the method was validated with cathepsin K knockdown using small interfering RNA (siRNA) transfection of human monocyte-derived macrophages, and enzymatic activity confirmed with benzyloxycarbonyl-glycine-proline-arginine-7-amino-4-methylcoumarin (Z-GPR-AMC) substrate hydrolysis was fit to a computational model of enzyme kinetics. Furthermore, cathepsin K zymography was used to show that murine osteoclasts secrete more cathepsin K than is stored intracellularly, and this was opposite to the behavior of the macrophages from which they were differentiated. In summary, this inexpensive, species-independent, antibody-free protocol describes a sensitive method with broad potential to elucidate previously undetectable cathepsin K activity.
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PMID:Detection of femtomole quantities of mature cathepsin K with zymography. 2020 19

Given the increasing prevalence of human obesity worldwide, there is an urgent need for a better understanding of the molecular mechanisms linking obesity to metabolic and cardiovascular diseases. Our knowledge is nevertheless limited regarding molecules linking adipose tissue to downstream complications. The importance of cathepsins was brought to light in this context. Through a large scale transcriptomic analysis, our group recently identified the gene encoding cathepsin S as one of the most deregulated gene in the adipose tissue of obese subjects and positively correlated with body mass index. Other members of the cathepsin family are expressed in the adipose tissue, including cathepsin K and cathepsin L. Given their implication in atherogenesis, these proteases could participate into the well established deleterious relationship between enlarged adipose tissue and increased cardiovascular risk. Here, we review the clinical and experimental evidence relevant to the role of cathepsins K, L and S and their most abundant endogenous inhibitor, cystatin C, in atherosclerosis and in obesity.
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PMID:Cathepsins and cystatin C in atherosclerosis and obesity. 2041 81


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