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• W2002263377 abstract "HomeCirculationVol. 125, No. 12Role for Cysteine Protease Cathepsins in Heart Disease Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBRole for Cysteine Protease Cathepsins in Heart DiseaseFocus on Biology and Mechanisms With Clinical Implication Xian Wu Cheng, MD, PhD, Guo-Ping Shi, DSc, Masafumi Kuzuya, MD, PhD, Takeshi Sasaki, PhD, Kenji Okumura, MD, PhD and Toyoaki Murohara, MD, PhD Xian Wu ChengXian Wu Cheng From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (X.W.C., K.O., T.M.); Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (G.-P.S.); Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya Japan (M.K.); Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, Hamamatsu, Japan (T.S.); Department of Cardiology, Yanbian University Hospital, Yanji, China (X.W.C.); and Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea (X.W.C.). Search for more papers by this author , Guo-Ping ShiGuo-Ping Shi From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (X.W.C., K.O., T.M.); Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (G.-P.S.); Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya Japan (M.K.); Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, Hamamatsu, Japan (T.S.); Department of Cardiology, Yanbian University Hospital, Yanji, China (X.W.C.); and Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea (X.W.C.). Search for more papers by this author , Masafumi KuzuyaMasafumi Kuzuya From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (X.W.C., K.O., T.M.); Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (G.-P.S.); Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya Japan (M.K.); Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, Hamamatsu, Japan (T.S.); Department of Cardiology, Yanbian University Hospital, Yanji, China (X.W.C.); and Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea (X.W.C.). Search for more papers by this author , Takeshi SasakiTakeshi Sasaki From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (X.W.C., K.O., T.M.); Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (G.-P.S.); Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya Japan (M.K.); Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, Hamamatsu, Japan (T.S.); Department of Cardiology, Yanbian University Hospital, Yanji, China (X.W.C.); and Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea (X.W.C.). Search for more papers by this author , Kenji OkumuraKenji Okumura From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (X.W.C., K.O., T.M.); Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (G.-P.S.); Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya Japan (M.K.); Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, Hamamatsu, Japan (T.S.); Department of Cardiology, Yanbian University Hospital, Yanji, China (X.W.C.); and Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea (X.W.C.). Search for more papers by this author and Toyoaki MuroharaToyoaki Murohara From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (X.W.C., K.O., T.M.); Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (G.-P.S.); Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya Japan (M.K.); Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, Hamamatsu, Japan (T.S.); Department of Cardiology, Yanbian University Hospital, Yanji, China (X.W.C.); and Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea (X.W.C.). Search for more papers by this author Originally published27 Mar 2012https://doi.org/10.1161/CIRCULATIONAHA.111.066712Circulation. 2012;125:1551–1562IntroductionThe extracellular matrix (ECM) of the heart is composed largely of elastin and collagen and plays many roles in cardiac wall and valve homeostasis. Maintenance of a healthy cardiac system relies on controlled biosynthesis, maturation, function, and breakdown of ECM proteins. Dysregulation of proteolytic enzymes may disrupt these normal biological processes in myocardium-coronary-valve disease (CCVD). Substantial evidence supports the involvement of matrix metalloproteinase (MMP) and serine protease families in this process (reviewed elsewhere1,2). Cysteinyl proteases have received much less consideration in this regard, even though cardiovascular cells and macrophages with greatly expanded lysosomal compartments figure prominently in the pathogenesis of CCVD.Lysosomal cysteine proteases, generally known as cathepsins, were discovered in the second half of the 20th century. In the initial years after their discovery, cysteinyl cathepsins were shown to localize in lysosomes and endosomes and to function there to degrade unwanted intracellular or endocytosed proteins.3–5 However, the recent recognition of the inducible cathepsins F, K, S, B, and L led to the unraveling of their molecular functions in inflammatory and/or autoimmune diseases such as atherosclerosis,6–11 obesity,12–14 rheumatoid arthritis,15,16 cardiac repair,17 cardiomyopathy,18–20 and cancer.21 Most strikingly, we have now discovered that these cathepsins can be secreted into and function within the extracellular spaces. The observations of cathepsin expression and activity in failing cardiac tissues22–24 and valve tissues25–27 from humans and animals and in cultured media of cardiomyocytes,22,24 cardiac fibroblasts,22 vascular smooth muscle cells,28 endothelial cells,12 and macrophages6,10 have significantly broadened our understanding of their potential roles in cardiovascular pathogenesis. Furthermore, recent studies have shown that pharmacological cathepsin inhibition exhibits cardiovascular protective actions in animal models.23,24 In addition, accumulating evidence shows a prognostic and diagnostic impact of circulating and tissue cathepsins and/or the endogenous inhibitors known as cystatins in cardiovascular injury, remodeling, and function.8,14 This review focuses on recent findings in this field, highlighting the cathepsin biology and the significance of lysosomal cysteinyl proteases in ECM remodeling, pharmacological intervention, and prediction of the development and progression of heart disease.Biology of Cysteinyl CathepsinsThe Properties and General Structure of Cysteinyl CathepsinsModern molecular biology has permitted the identification of various characterization of cysteinyl protease cathepsins, including the following: (1) Cathepsins have a high homology with members of the papain family29; (2) they comprise mainly endopeptidases with a few exceptions (cathepsin B, exopeptidase; cathepsin H, aminopeptidase)3,30–32; (3) they are synthesized as glycosylated precursors that are activated by removal of the N-terminal propeptide by other proteinases or autocatalysis33; (4) they have a broad substrate specificity for cell matrix components and can degrade almost all intracellular and extracellular proteins through their combined activities (Table 1); (5) their activity is regulated intracellularly by a specific endogenous inhibitor cystatin subgroup called stefins (stefin A and B) and extracellularly by cystatins (cystatin C) and kininogens34; and (6) they have cell- or tissue type–specific (as in cathepsins F, S, and K)15,35–37 and nonspecific (cathepsins B, H, and L)38,39 expression patterns. In humans, cathepsin cysteine proteases consist of a family of 11 members (cathepsins B, C, F, H, K, L, O, S, V, W, and Z).40 In mice, 19 cathepsins have been discovered, including several additional placentally expressed cathepsins with no human homolog.41 As described in a previous review, most of these cathepsins are relatively small proteins with Mr values in the range of 20 000 to 35 000.4 Human cathepsins have been shown to share a conserved active 3-dimensional pocket formed with histidine, asparagine, and cysteine residues.21,40,42 At its N-terminus structure, cathepsin contains a small minidomain, which forms a small compact structure, and an extended peptide, which is bound over the active site clef, occluding it.39 As shown in models of the primary cathepsin structure, the cathepsin contains a signaling peptide, proregion, heavy chain, and light chain (Figure 1A). The D-dimensional structures of cysteinyl cathepsins show that all enzymes share a common fold.43 Analysis of the crystal structure of cathepsin L shows that the mature enzymes consist of 2 domains separated by a V-shaped active site cleft where Cys25 and His163 form the catalytic site.29 In contrast, aminopeptidase cathepsin H has been shown to use the minichain, an 8-residue-long peptide originating from the propeptide region, which binds into the nonprimed region of the active site cleft in a substrate orientation.3,44 These findings suggested that the binding sites within the active site cleft provide the structural basis for understanding the enzyme specificity. This notion is further supported by the observations29,33,45 that the crystal structure of cathepsins in complex with the major histocompatibility class II-p41 Ii fragment provides the basis for differentiation between the structurally highly similar cathepsins S and L, thus contributing to a better understanding of the role of these 2 enzymes in antigen processing and presentation.Table 1. Cathepsin Expression in Cardiovascular and Other Cells: Its Regulation, Substrates, and EventsCathepsinsGene Expression Stimulatory FactorsSubstratesECM Degradation Assay In Vitro/In VivoCathepsin BAng II, IL-1β, TNF-α, IFN-γPlasminogen, antiapoptotic molecules (Bcl-2, Bcl-xL, Mcl-1, and XLAP)−/−Cathepsin SAng II, IL-1β, TNF-α, IFN-γ, VEGF, bFGF, H2O2Elastin, collagen, fibronectin, laminin, MHC class II Ii+/+Cathepsin KAng II, IL-1β, TNF-α, IFN-γElastin, collagen+/+Cathepsin LIL-1β, TNF-α, VEGF, bFGF, glucoseProhormones, MHC class II Ii, trypsinogen+/+Cystatin CAng II, IL-1β, TNF-α, IFN-γ, H2O2+/+EMC indicates extracellular matrix; Ang II, angiotensin II; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; XLAP, X-chromosome-linked inhibitor of apoptosis; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; MHC, major histocompatibility class; +, genetic mice report or genetic mice–derived cell assay; and −, no genetic mice report.Download figureDownload PowerPointFigure 1. A model of the cathepsin primary structure and cathepsin maturation processes. A, Cathepsin contains a signaling peptide, proregion, heavy chain, and light chain. B, The cathepsin maturation process is as follows: synthesis→targeting to endoplasmic reticulum (ER)→signal peptide removing/folding and disulfide-bound formation/glycosylation (ER)→mannose-6 residue phosphorylation (m6p; Golgi)→acidification (early endosome)→proregion removing (endosome)→further activation (heavy and light chains, endosome)→Ca2+-mediated organelle fusion and secretion into extracellular spaces. It should be noted that, during processing, a portion of cathepsins are shunted into the exocytosis pathway without converting to the m6p form. C, Cathepsin forms that lack the signal peptide-associated alternative splicing and exon skipping-related translation targeted to the cytosol, nucleus, and mitochondrial matrix. TGN indicates trans-Golgi network.Maturation of Cysteinyl Cathepsin From Synthesis to ActivationCathepsins have been known to synthesize as proenzymes with an N-terminal signaling peptide that targets the protein to the lumen of the endoplasmic reticulum.46,47 Cathepsins destined for the lysosome are further processed in the Golgi apparatus by modification of mannose residues to mannose-6-phosphate (reviewed previously39). After this modification, cathepsins bind to the mannose-6-phosphate receptor for targeting to the lysosome and to activation.48,49 Proteolytic activation is accomplished by the action of different proteases such as pepsin, neutrophil elastase, cathepsin D, and various cysteine proteases.47,50 From the results of previous studies,51,52 Reiser and colleagues39 proposed that active cathepsins might be recruited from late endosomes or lysosomes for secretion into the extracellular space through Ca2+-dependent fusion of these organelles with the cell membrane. Limited activation is thus a crucial step in controlling the activity of cathepsins.53 Partial or complete removal of the proregion during activation affects the stability and folding of the enzymes.54,55 Increasing evidence indicates that the proregion plays an important role in the inhibition of cathepsin activity.29,56 The cathepsin maturation from synthesis to activation is represented schematically in Figure 1B.Regulation of Cysteinyl CathepsinSimilar to members of the MMP family, the cathepsins are regulated at 3 levels: via the gene, activation, and activity. The activity of cathepsins can be controlled in a number of ways, two of the most important being through specific precursor activation mechanisms and through the specific regulation of mature enzymes by pH and inhibition by their endogenous protein inhibitors.3 It is well known that the activity of cathepsin is controlled mainly intracellularly by a specific cystatin subgroup called stefins and extracellularly by cystatins and kininogens.34 Significant differences will most likely occur at the N- or C-terminal parts of the prosegment.33 A future investigation is needed to identify the specificity determinants that allow the propeptides to differentiate between closely related members of the papain superfamily. The pH-mediated regulation has been covered by a recent comprehensive review.3In addition to the regulation of cathepsin activity level, transcriptional regulation has been studied with respect to transcriptional factors. A gene expression assay suggested that the Sp1 and Sp3 transcriptional factors binding to GC boxes can regulate several cathepsins, including cathepsins B57 and L.58 Ets family transcription factors have been linked to transcriptional regulation of cysteine cathepsins and MMPs and serine proteases (reviewed previously21,57). On the other hand, over the past decade, there have been several reports of transcript variants arising from the use of alternative promoters and alternative splicing for cathepsins B59 and L.21,60 Most strikingly, recent reports suggested that alternative slicing and exon skipping can produce a complete absence of signaling peptide on cathepsins and accumulation into the nucleus and mitochondrial matrix (Figure 1C).39,60,61 Truncated cathepsin L has been identified as causing loss of integrity of the glomerular filtration barrier owing to proteolyzing dynamin in podocytes.62 In the meantime, additional cleavage substrates for cytosolic cathepsin L have been found, ie, synaptopodin63 and CD2AP.64 However, elucidation of the transcription variants and transcriptional regulation of these enzymes in cardiovascular disease requires further study. The regulation of cathepsin expression in cardiac and vascular cells is summarized in Table 1 and Figure 2.Download figureDownload PowerPointFigure 2. The cathepsin cysteine proteases known to be expressed in cardiovascular and valve cells and myocardium-coronary-valve disease (CCVD)–associated cells and have been identified as contributing to the initiation and progression of CCCVD. A, Macroscopy of whole heart. B, Microscopy of the myocardium. Scale bar=50 μm. Cats indicates cathepsins; CFC, cardiac myofibroblast; CMC, cardiomyocytes; and EC, endothelial cell.Cellular Expression of Cysteine CathepsinsLike most MMPs, neonatal cardiomyocytes express negligible levels of cathepsin S under basal conditions.22 However, incubation of these cells with tumor necrosis factor-α and interleukin-1β markedly augments cathepsin S gene and protein expression. These cytokines also increased the levels of the cathepsin K, B, and L mRNAs.22 Similar to the cardiomyocytes, both cytokines stimulated the levels of the cathepsin S and B genes in cultured cardiac fibroblasts or/and myofibroblasts.22,26 Furthermore, angiotensin II and superoxide markedly upregulated the levels of cathepsin S expression and activity in cultured cardiomyocytes; these changes were moderated by an antioxidative agent.24 Superoxide has also been shown to stimulate the elevation of cystatin C protein in the conditioned medium of cardiomyocytes.65 These findings suggest that cathepsins derived from cardiac cells can participate in the pathogenesis of cardiac injury in response to inflammation and oxidative stress. The expression patterns of cathepsins in cardiovascular-valve cells and CCVD-related cells are summarized in Figure 2.Proteolytic Activities of Cysteinyl CathepsinsAfter synthesis, cathepsins are relocated to the acidic compartments, lysosomes and endosomes, through either the mannose-6-phosphate receptor–dependent or –independent pathways, where the enzymes are activated to function in unwanted substrate metabolism.48,49 These organelles give cathepsins the optimum pH for their activity.35 Our data and those of other investigators have demonstrated the presence and activity (collagenolytic and/or elastolytic) of these proteases in media conditioned by endothelial cells, smooth muscle cells, neonatal cardiomyocytes, and macrophages.6–8,66 These findings raise several questions concerning the release and extracellular activity of these proteases because most of them exit within a very narrow optimal acidic pH in the organelles.67 Previous observations suggested that cathepsins K and L can lose their activity at neutral pH.68 In contrast to these enzymes, cathepsin S has been shown to retain a pronounced level of activity at neutral pH.69 However, it is questionable whether this partial activity can satisfactorily explain all of the cathepsin-dependent ECM degradation observed in vitro. Recently, Punturieri et al70 have proposed the hypothesis that the focal contact can permit cysteine proteases to degrade ECM proteins efficiently. They showed the formation of a localized acidic environment in a zone of contact that excludes the surrounding extracellular milieu in human monocyte-derived macrophages. Lysosomal H+-ATPase has been shown to translocate across the plasma membrane and to create a localized acidic environment for lysosomal secretions in macrophages.71 These findings provide a reasonable explanation for ECM degradation by cysteine proteases in cardiovascular tissues. Additionally, modern molecular biological techniques have allowed the characterization of novel functions of cathepsins, including a wide range of contributions to prohormone processing,72 neuropeptide biosynthesis and secretion,73,74 and inactivation of other proteases.75 More recently, we have recognized that cathepsin L can play a role in cell development and differentiation via histone modification.76,77 From these findings, we propose that both the traditional and the novel cathepsin functions work together or independently as mechanisms to contribute directly and indirectly to the initiation and progression of CCVD.On the other hand, many cellular events in the development of atherosclerosis-based cardiovascular disease depend on the cathepsin-mediated degradation of intracellular and extracellular proteins, including cell adhesion, transmigration, differentiation, proliferation, apoptosis, and neovascularization and antigen presentation (reviewed previously67,78). Although cathepsins are abundantly present in human and animal cardiac wall22 and valve tissues,25,26,79 the exact role each specific cathepsin plays in heart disease development and the mechanism and significance behind their function are largely unknown.Cathepsins and Cystatin C in CCVDThe pathogenesis of heart disease involves substantial proteolysis of the ventricular and valvular extracellular proteins. Different families of proteolytic enzymes may participate in this process, including MMPs, serine proteases, and cysteinyl cathepsins. The roles of proteolytic enzymes in various cardiovascular diseases have been covered by recent comprehensive reviews.1,2Next, we consider the role of cathepsins in CCVD in greater detail. The sections below describe the cathepsins involved in several myocardial, coronary, and valve diseases, especially with respect to their potential application as diagnostic and/or prognostic markers and drug targets to prevent CCVD.Cathepsins in Hypertensive Cardiac Hypertrophy and FailureThe expression patterns of cathepsins in cardiovascular cells and CCVD-related cells are summarized in Figure 2. Hypertension refers to enhanced arteriole pressure and total peripheral artery resistance as a result of hemodynamic overload on the heart and is known to cause cardiac hypertrophy, fibrosis, remodeling, and heart failure (HF; reviewed elsewhere1,80).An in vitro study reported that cathepsin is expressed in cultured rat neonatal cardiomyocytes and cardiac fibroblasts.22 The gene and protein levels of cathepsin S and/or K were markedly upregulated by tumor necrosis factor-α and interleukin-1β, which were increased in the failing rat myocardium in association with hypertension, in cultured neonatal cardiomyocytes, and in fibroblasts.22 Angiotensin II and H2O2 have also been shown to affect the expression of enzymes.24 Changes in protease expression and activity have been shown to occur in hypertension; the levels of the cathepsin S, B, and K genes have been shown to be increased in the hypertrophic and failing myocardium, whereas those of cystatin C showed no significant changes in Dahl salt-sensitive rats, a model of hypertension.22 Immunohistochemical analysis revealed only a low level of expression of cathepsins S and K in the myocardium of control rats.22 In contrast, the expression of these enzymes was markedly increased throughout the myocardium of rats with hypertensive HF, with staining apparent in cardiac myocytes, intracoronary smooth muscle cells, and dispersed macrophages. Furthermore, the elastase assays demonstrated that the levels of cathepsins S and K increased significantly with increasing elastolytic activity in the tissue extracts from the failing rat myocardium; this response was blunted by the broad-spectrum cysteine protease inhibitor trans-epoxysuccinyl-l-leucylamido-(4-guanidino) butane (E64) or a specific inhibitor of cathepsin S, morpholinurea-leucine-homophenylalanine-vinylsulfonephenyl.22,24 Similar to the findings in the rat model, the amounts of cathepsins S and K were found to be increased in the failing myocardium of patients with hypertensive HF.22 Active cathepsins S, K, and L have been shown to degrade ECM proteins, including laminin,81 fibronectin,82 elastin,66 and collagens.15,28 It is well known that MMPs can degrade all of the ECM proteins and activate cysteine cathepsins.2 Together, these various findings support the notion that cathepsins may participate in cardiac remodeling by mediating ECM degradation in cooperation with other proteases such as MMPs and serine proteases.Cathepsins in CardiomyopathyMore than a decade ago, it was reported that defects in lysosomes and lysosomal proteases cause heterogeneous heart diseases such as cardiomyopathies.18–20 In humans, cathepsin B mRNA and protein levels are greater in dilated cardiomyopathy than in control hearts.83 Here, we have observed that the levels of cathepsins S, B, L, and/or K were increased in subjects with dilated and hypertrophic cardiomyopathies compared with control subjects (Figure 3A). Similar to cathepsins, cystatin C also showed a change in the failing myocardium of subjects with either type of cardiomyopathy. On the other hand, among cysteine cathepsins, the protein with the most extensively described role in the health and disease of the heart is cathepsin L.39 Cathepsin L is a ubiquitously expressed lysosomal cysteine proteinase that is primarily responsible for intracellular protein degradation.84 Genetic studies have revealed that, unlike other cathepsin-deficient (Cts−/−) animals, aging cathepsin L Ctsl−/− mice develop interstitial myocardial fibrosis and show pleomorphic nuclei in cardiomyocytes; both signs are characteristic of human cardiomyopathies (Table 2).18–20 These changes are associated with cardiac chamber dilation and impaired cardiac function. Moreover, abnormal heart rhythms (supraventricular tachycardia, ventricular extrasystoles, and first-degree atrioventricular block) are detected in older Ctsl−/− mice (Table 2).19 Cardiomyocytes from Ctsl−/− newborn mice show impaired endolysosomal systems.19 Cathepsin L deficiency slows autophagolysosome turnover and results in accumulation of dysmorphic and acidic organelles.85 These findings, coupled with findings that defects in the acidic cellular compartments are accompanied by complex biochemical and mitochondrial impairment,19 raise the question of how cathepsin L deficiency and alterations of the acidic compartments change intracellular signaling to induce cardiac hypertrophic action and ventricular chamber dilation. The role of homeostatic cysteine cathepsin L in cardiomyopathy has been the subject of a review39 and therefore is not discussed in detail here.Download figureDownload PowerPointFigure 3. Expression of cathepsin mRNAs in cardiac tissues. A, Upregulation of expression of mRNAs of cathepsins and cystatin C in patients with dilated cardiomyopathy (DCM; n=24) or hypertrophic cardiomyopathy (HCM; n=18) compared with controls (n=7). B, Representative images of increased expression of angiotensin II type 1 receptor (AT1R; rabbit polyclonal anti-AT1R) and cathepsin S (Cat S; rabbit polyclonal anti-human Cat S) and the levels of macrophage infiltration (mouse monoclonal anti-rat CD68; Chemicon, Temecula, CA) and superoxide production (using dihydroethidium [DHE] staining) in the myocardium and/or intracoronary arteries with hypertensive heart failure (H-HF). Arrowheads indicate relatively positively staining cells. Values are mean±SEM. *P<0.05, **P<0.01 vs controls. C, Colocalization of Cat S and AT1R in human coronary atherosclerotic lesions. Scale bars=50 μm.Table 2. Cardiac Phenotypes of Genetically Altered MiceGenotypeHeart PhenotypehCtsl-TGCardiac response (in vivo aortic banding model): decreased hypertrophic response, apoptosis, and fibrosisIn vitro experiment: blunted cardiomyocyte hypertrophy via Akt/GSK3β signalingCtsl−/−Intracellular (1 y old): Multiple large and fused lysosomes, storage of electron-dense heterogeneous material, and turnover of autophagolysosomes and acidic vesicles; pleomorphic nuclei; loss of cytoskeletal proteins; mitochondrial dysfunctionExtracellular (1 y old): interstitial fibrosisCardiac expression: cardiac chamber dilation and dysfunction, abnormal heart rhythms (SPVT, VEs, first-degree AV block)Ctsl−/−Cardiac repair (postinfarction): decreased inflammatory response and levels of G-CSF, SCF, and SDF-1 proteins, fibrosis, myofibroblast deposition, neovascularization, bone marrow cell mobilization, c-kit–positive cells, natural killer cells, fibrocytes, and monocytes in cardiac tissueshCtsl-TG indicates human cathepsin L transgenic; Ctsl−/−, cathepsin L deficiency; SPVT, supraventricular tachycardia; VEs, ventricular extrasystoles; AV, atrioventricular; G-CSF, granulocyte colony stimulating factor; SCF, stem cell factor; and SDF-1, stromal-cell-derived factor-1.The role of cathepsin in physiological autophagy and pathological apoptosis in cardiac disease has been investigated in several animal studies.86,87 Sehl et al87 reported that cathepsin B was overexpressed in the necrotic regions of the myocardium. It has been reported that cathepsin B participates in apoptosis of serum deprivation–induced PC12 cells. An absence of cathepsins B and L has been shown to induce neuronal loss and brain atrophy.88 In contrast, endogenous cystatin C inhibitor overexpression induced neuronal cell death associated with caspase-3 activation in vivo and in vitro.89 Furthermore, Yu et al90 reported that cystatin C–deficient mice exhibited increased cathepsin L expression and activity and reduced epithelial apoptosis. The antiapoptotic molecules Bcl-2, Bcl-xL, Mcl-1, and XLAP (X-chromosome-linked inhibitor of apoptosis) are targeted by the lysosomal cathepsins B and L in several human cancer cell lines.91 Collectively, these findings indicate that cathepsin-deficient–mediated cardiomyopathy might be attributable to the caspase-dependent and -independent apoptosis in mice. The involvement of cathepsins in autophagy and apoptosis is summarized in Table 3.Table 3. Cathepsin Cellular Functions and Clinical ApplicationsCathepsinsAutophagy/ApoptosisBiomarker/Imaging ToolDrug TargetRelated DiseaseCathepsin B+/−−/+−Cardiac diseaseCoronary diseaseCathepsin S−/−+/++Cardiac diseaseCoronary diseaseValve diseaseCathepsin K−/−−/++Cardiac diseaseCoronary diseaseValve diseaseCathepsin L−/++/+−Cardiac diseaseCoronary diseaseCathepsin H−/−−/−−Cardiac diseaseCystatin C−/++/−+Cardiac diseaseCoronary disease+ Indicates available or reported; −, not available" @default.
• W2002263377 created "2016-06-24" @default.
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• W2002263377 date "2012-03-27" @default.
• W2002263377 modified "2023-09-30" @default.
• W2002263377 title "Role for Cysteine Protease Cathepsins in Heart Disease" @default.
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