Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cysteine protease cathepsins in cardiovascular disease: from basic research to clinical trials

Nature Reviews Cardiology volume 15, pages 351–370 (2018)Cite this article

Subjects

Abstract

Cysteine protease cathepsins have traditionally been considered as lysosome-restricted proteases that mediate proteolysis of unwanted proteins. However, studies from the past decade demonstrate that these proteases are localized not only in acidic compartments (endosomes and lysosomes), where they participate in intracellular protein degradation, but also in the extracellular milieu, plasma membrane, cytosol, nucleus, and nuclear membrane, where they mediate extracellular matrix protein degradation, cell signalling, and protein processing and trafficking through the plasma and nuclear membranes and between intracellular organelles. Studies in experimental disease models and on cathepsin-selective inhibitors, as well as plasma and tissue biomarker data from animal models and humans, have verified the participation of cysteinyl cathepsins in the pathogenesis of many cardiovascular diseases, including atherosclerosis, myocardial infarction, cardiac hypertrophy, cardiomyopathy, abdominal aortic aneurysms, and hypertension. Clinical trials of cathepsin inhibitors in chronic inflammatory diseases suggest the utility of these inhibitors for the treatment of cardiovascular diseases and associated complications. Moreover, development of cell transfer technologies that enable ex vivo cell treatment with cathepsin inhibitors might limit the unwanted systemic effects of cathepsin inhibition and provide new avenues for targeting cysteinyl cathepsins. In this Review, we summarize the available evidence implicating cysteinyl cathepsins in the pathogenesis of cardiovascular diseases, discuss their potential as biomarkers of disease progression, and explore the potential of cathepsin inhibitors for the treatment of cardiovascular diseases.

Key points

  • Cysteine protease cathepsins act beyond the lysosomes and have widespread physiological and pathological actions, although some cysteinyl cathepsins show tissue-specificity or cell-type-specificity.

  • Cathepsin activity is generally increased in the heart and arterial wall in patients with cardiovascular diseases, and studies in mouse models have established the participation of cathepsins B, C, K, L, and S, and their endogenous inhibitor cystatin C, in various cardiovascular diseases.

  • Cathepsin actions in cardiovascular diseases include the regulation of cell–cell interactions, intracellular signalling, protein expression, angiogenesis, cholesterol metabolism, cell migration, and apoptosis.

  • Cathepsins contribute to cardiovascular inflammation directly and indirectly by regulating innate and adaptive immunity.

  • Plasma cathepsins and cystatins might serve as biomarkers of cardiovascular disease in humans.

  • The development of selective cathepsin antagonists and the results of their preliminary clinical evaluation warrant further clinical trials of cathepsin inhibitors for treatment of certain cardiovascular conditions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Cathepsin activities in the vasculature.
Fig. 2: Cathepsin activities in the heart.
Fig. 3: Two potential mechanisms of extracellular space acidification.
Fig. 4: Cathepsin S-mediated leukocyte recruitment.
Fig. 5: Cytosolic cathepsins and cell death.
Fig. 6: Cathepsin roles in inflammasome activation.

Similar content being viewed by others

References

  1. Chapman, H. A., Riese, R. J. & Shi, G. P. Emerging roles for cysteine proteases in human biology. Annu. Rev. Physiol. 59, 63–88 (1997).

    Article  PubMed  CAS  Google Scholar 

  2. Dubin, G. Proteinaceous cysteine protease inhibitors. Cell. Mol. Life Sci. 62, 653–669 (2005).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Howie, A. J., Burnett, D. & Crocker, J. The distribution of cathepsin B in human tissues. J. Pathol. 145, 307–314 (1985).

    Article  PubMed  CAS  Google Scholar 

  4. Bando, Y., Kominami, E. & Katunuma, N. Purification and tissue distribution of rat cathepsin L. J. Biochem. 100, 35–42 (1986).

    Article  PubMed  CAS  Google Scholar 

  5. Shi, G. P. et al. Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2. FEBS Lett. 357, 129–134 (1995).

    Article  PubMed  CAS  Google Scholar 

  6. Wang, B. et al. Human cathepsin F. Molecular cloning, functional expression, tissue localization, and enzymatic characterization. J. Biol. Chem. 273, 32000–32008 (1998).

    Article  PubMed  CAS  Google Scholar 

  7. Shi, G. P. et al. Role for cathepsin F in invariant chain processing and major histocompatibility complex class II peptide loading by macrophages. J. Exp. Med. 191, 1177–1186 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Shi, G. P. et al. Human cathepsin S: chromosomal localization, gene structure, and tissue distribution. J. Biol. Chem. 269, 11530–11536 (1994).

    PubMed  CAS  Google Scholar 

  9. Sukhova, G. K., Shi, G. P., Simon, D. I., Chapman, H. A. & Libby, P. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J. Clin. Invest. 102, 576–583 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Shi, G. P. et al. Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J. Clin. Invest. 104, 1191–1197 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Shi, G. P. et al. Cathepsin S required for normal MHC class II peptide loading and germinal center development. Immunity 10, 197–206 (1999).

    Article  PubMed  CAS  Google Scholar 

  12. Nakagawa, T. et al. Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 280, 450–453 (1998).

    Article  PubMed  CAS  Google Scholar 

  13. Sun, J. et al. Deficiency of antigen-presenting cell invariant chain reduces atherosclerosis in mice. Circulation 122, 808–820 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Ewald, S. E. et al. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456, 658–662 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Zhou, Y. et al. Cathepsin K Deficiency ameliorates systemic lupus erythematosus-like manifestations in Faslpr mice. J. Immunol. 198, 1846–1854 (2017).

    Article  PubMed  CAS  Google Scholar 

  16. Taleb, S., Tedgui, A. & Mallat, Z. Regulatory T-cell immunity and its relevance to atherosclerosis. J. Intern. Med. 263, 489–499 (2008).

    Article  PubMed  CAS  Google Scholar 

  17. Sharir, R. et al. Experimental myocardial infarction induces altered regulatory T cell hemostasis, and adoptive transfer attenuates subsequent remodeling. PLoS ONE 9, e113653 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Zhou, Y. et al. Regulatory T cells in human and angiotensin II-induced mouse abdominal aortic aneurysms. Cardiovasc. Res. 107, 98–107 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Cheng, X. W. et al. Role for cysteine protease cathepsins in heart disease: focus on biology and mechanisms with clinical implication. Circulation 125, 1551–1562 (2012).

    Article  PubMed  Google Scholar 

  20. Keegan, P. M., Surapaneni, S. & Platt, M. O. Sickle cell disease activates peripheral blood mononuclear cells to induce cathepsins k and v activity in endothelial cells. Anemia 2012, 201781 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Jiang, H. et al. Cathepsin K-mediated Notch1 activation contributes to neovascularization in response to hypoxia. Nat. Commun. 5, 3838 (2014).

    Article  PubMed  CAS  Google Scholar 

  22. Platt, M. O. et al. Expression of cathepsin K is regulated by shear stress in cultured endothelial cells and is increased in endothelium in human atherosclerosis. Am. J. Physiol. Heart Circ. Physiol. 292, H1479–1486 (2007).

    Article  PubMed  CAS  Google Scholar 

  23. Liu, J. et al. Lysosomal cysteine proteases in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 24, 1359–1366 (2004).

    Article  PubMed  CAS  Google Scholar 

  24. Oorni, K. et al. Cysteine protease cathepsin F is expressed in human atherosclerotic lesions, is secreted by cultured macrophages, and modifies low density lipoprotein particles in vitro. J. Biol. Chem. 279, 34776–34784 (2004).

    Article  PubMed  CAS  Google Scholar 

  25. Liu, J. et al. Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis, and vascular cells. Atherosclerosis 184, 302–311 (2006).

    Article  PubMed  CAS  Google Scholar 

  26. Yasuda, Y. et al. Cathepsin V, a novel and potent elastolytic activity expressed in activated macrophages. J. Biol. Chem. 279, 36761–36770 (2004).

    Article  PubMed  CAS  Google Scholar 

  27. Rodgers, K. J. et al. Destabilizing role of cathepsin S in murine atherosclerotic plaques. Arterioscler. Thromb. Vasc. Biol. 26, 851–856 (2006).

    Article  PubMed  CAS  Google Scholar 

  28. Abd-Elrahman, I. et al. Characterizing cathepsin activity and macrophage subtypes in excised human carotid plaques. Stroke 47, 1101–1108 (2016).

    Article  PubMed  CAS  Google Scholar 

  29. Liu, Y. et al. Usefulness of serum cathepsin L as an independent biomarker in patients with coronary heart disease. Am. J. Cardiol. 103, 476–481 (2009).

    Article  PubMed  CAS  Google Scholar 

  30. Liu, J. et al. Increased serum cathepsin S in patients with atherosclerosis and diabetes. Atherosclerosis 186, 411–419 (2006).

    Article  PubMed  CAS  Google Scholar 

  31. Li, W., Kornmark, L., Jonasson, L., Forssell, C. & Yuan, X. M. Cathepsin L is significantly associated with apoptosis and plaque destabilization in human atherosclerosis. Atherosclerosis 202, 92–102 (2009).

    Article  PubMed  CAS  Google Scholar 

  32. Mattock, K. L. et al. Legumain and cathepsin-L expression in human unstable carotid plaque. Atherosclerosis 208, 83–89 (2010).

    Article  PubMed  CAS  Google Scholar 

  33. Lutgens, E. et al. Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation. Circulation 113, 98–107 (2006).

    Article  PubMed  CAS  Google Scholar 

  34. Jaffer, F. A. et al. Optical visualization of cathepsin K activity in atherosclerosis with a novel, protease-activatable fluorescence sensor. Circulation 115, 2292–2298 (2007).

    Article  PubMed  CAS  Google Scholar 

  35. Barascuk, N. et al. Human macrophage foam cells degrade atherosclerotic plaques through cathepsin K mediated processes. BMC Cardiovasc. Disord. 10, 19 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Samokhin, A. O., Wong, A., Saftig, P. & Bromme, D. Role of cathepsin K in structural changes in brachiocephalic artery during progression of atherosclerosis in apoE-deficient mice. Atherosclerosis 200, 58–68 (2008).

    Article  PubMed  CAS  Google Scholar 

  37. Jaffer, F. A. et al. Real-time catheter molecular sensing of inflammation in proteolytically active atherosclerosis. Circulation 118, 1802–1809 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Sukhova, G. K. et al. Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. J. Clin. Invest. 111, 897–906 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. de Nooijer, R. et al. Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 29, 188–194 (2009).

    Article  PubMed  CAS  Google Scholar 

  40. Samokhin, A. O., Lythgo, P. A., Gauthier, J. Y., Percival, M. D. & Bromme, D. Pharmacological inhibition of cathepsin S decreases atherosclerotic lesions in Apoe−/− mice. J. Cardiovasc. Pharmacol. 56, 98–105 (2010).

    Article  PubMed  CAS  Google Scholar 

  41. Wu, H. et al. Cathepsin S activity controls injury-related vascular repair in mice via the TLR2-mediated p38MAPK and PI3K-Akt/p-HDAC6 signaling pathway. Arterioscler. Thromb. Vasc. Biol. 36, 1549–1557 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Shi, H. T. et al. Cathepsin S contributes to macrophage migration via degradation of elastic fibre integrity to facilitate vein graft neointimal hyperplasia. Cardiovasc. Res. 101, 454–463 (2014).

    Article  PubMed  CAS  Google Scholar 

  43. Figueiredo, J. L. et al. Selective cathepsin S inhibition attenuates atherosclerosis in apolipoprotein E-deficient mice with chronic renal disease. Am. J. Pathol. 185, 1156–1166 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Kitamoto, S. et al. Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice. Circulation 115, 2065–2075 (2007).

    Article  PubMed  CAS  Google Scholar 

  45. Herias, V. et al. Leukocyte cathepsin C deficiency attenuates atherosclerotic lesion progression by selective tuning of innate and adaptive immune responses. Arterioscler. Thromb. Vasc. Biol. 35, 79–86 (2015).

    Article  PubMed  CAS  Google Scholar 

  46. Bengtsson, E. et al. Absence of the protease inhibitor cystatin C in inflammatory cells results in larger plaque area in plaque regression of apoE-deficient mice. Atherosclerosis 180, 45–53 (2005).

    Article  PubMed  CAS  Google Scholar 

  47. Abisi, S. et al. Cysteine protease activity in the wall of abdominal aortic aneurysms. J. Vasc. Surg. 46, 1260–1266 (2007).

    Article  PubMed  Google Scholar 

  48. Lv, B. J., Lindholt, J. S., Cheng, X., Wang, J. & Shi, G. P. Plasma cathepsin S and cystatin C levels and risk of abdominal aortic aneurysm: a randomized population-based study. PLoS ONE 7, e41813 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Lv, B. J., Lindholt, J. S., Wang, J., Cheng, X. & Shi, G. P. Plasma levels of cathepsins L, K, and V and risks of abdominal aortic aneurysms: a randomized population-based study. Atherosclerosis 230, 100–105 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Tung, W. S., Lee, J. K. & Thompson, R. W. Simultaneous analysis of 1176 gene products in normal human aorta and abdominal aortic aneurysms using a membrane-based complementary DNA expression array. J. Vasc. Surg. 34, 143–150 (2001).

    Article  PubMed  CAS  Google Scholar 

  51. van Vlijmen-van Keulen, C. J., Vahl, A. C., Hennekam, R. C., Rauwerda, J. A. & Pals, G. Genetic linkage of candidate genes in families with abdominal aortic aneurysms? Eur. J. Vasc. Endovasc. Surg. 26, 205–210 (2003).

    Article  PubMed  Google Scholar 

  52. Qin, Y. et al. Deficiency of cathepsin S attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice. Cardiovasc. Res. 96, 401–410 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Sun, J. et al. Cathepsin L activity is essential to elastase perfusion-induced abdominal aortic aneurysms in mice. Arterioscler. Thromb. Vasc. Biol. 31, 2500–2508 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Sun, J. et al. Cathepsin K deficiency reduces elastase perfusion-induced abdominal aortic aneurysms in mice. Arterioscler. Thromb. Vasc. Biol. 32, 15–23 (2012).

    Article  PubMed  CAS  Google Scholar 

  55. Schulte, S. et al. Cystatin C deficiency promotes inflammation in angiotensin II-induced abdominal aortic aneurisms in atherosclerotic mice. Am. J. Pathol. 177, 456–463 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Aoki, T., Kataoka, H., Ishibashi, R., Nozaki, K. & Hashimoto, N. Cathepsin B, K, and S are expressed in cerebral aneurysms and promote the progression of cerebral aneurysms. Stroke 39, 2603–2610 (2008).

    Article  PubMed  CAS  Google Scholar 

  57. Cheng, X. W. et al. Elastolytic cathepsin induction/activation system exists in myocardium and is upregulated in hypertensive heart failure. Hypertension 48, 979–987 (2006).

    Article  PubMed  CAS  Google Scholar 

  58. Mehra, S. et al. Clinical significance of cathepsin L and cathepsin B in dilated cardiomyopathy. Mol. Cell Biochem. 428, 139–147 (2017).

    Article  PubMed  CAS  Google Scholar 

  59. Helske, S. et al. Increased expression of elastolytic cathepsins S, K, and V and their inhibitor cystatin C in stenotic aortic valves. Arterioscler. Thromb. Vasc. Biol. 26, 1791–1798 (2006).

    Article  PubMed  CAS  Google Scholar 

  60. Chen, H. et al. Cathepsin S-mediated fibroblast trans-differentiation contributes to left ventricular remodelling after myocardial infarction. Cardiovasc. Res. 100, 84–94 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Pan, L. et al. Cathepsin S deficiency results in abnormal accumulation of autophagosomes in macrophages and enhances Ang II-induced cardiac inflammation. PLoS ONE 7, e35315 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Aikawa, E. et al. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease. Circulation 119, 1785–1794 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Stypmann, J. et al. Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L. Proc. Natl Acad. Sci. USA 99, 6234–6239 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Spira, D. et al. Cell type-specific functions of the lysosomal protease cathepsin L in the heart. J. Biol. Chem. 282, 37045–37052 (2007).

    Article  PubMed  CAS  Google Scholar 

  65. Sun, M. et al. Cathepsin-L contributes to cardiac repair and remodelling post-infarction. Cardiovasc. Res. 89, 374–383 (2011).

    Article  PubMed  CAS  Google Scholar 

  66. Sun, M. et al. Cathepsin-L ameliorates cardiac hypertrophy through activation of the autophagy-lysosomal dependent protein processing pathways. J. Am. Heart Assoc. 2, e000191 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Tang, Q. et al. Lysosomal cysteine peptidase cathepsin L protects against cardiac hypertrophy through blocking AKT/GSK3beta signaling. J. Mol. Med. 87, 249–260 (2009).

    Article  PubMed  CAS  Google Scholar 

  68. Hua, Y. et al. Cathepsin K knockout mitigates high-fat diet-induced cardiac hypertrophy and contractile dysfunction. Diabetes 62, 498–509 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Hua, Y. et al. Cathepsin K knockout alleviates pressure overload-induced cardiac hypertrophy. Hypertension 61, 1184–1192 (2013).

    Article  PubMed  CAS  Google Scholar 

  70. Hua, Y. et al. Cathepsin K knockout alleviates aging-induced cardiac dysfunction. Aging Cell 14, 345–351 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Liu, A., Gao, X., Zhang, Q. & Cui, L. Cathepsin B inhibition attenuates cardiac dysfunction and remodeling following myocardial infarction by inhibiting the NLRP3 pathway. Mol. Med. Rep. 8, 361–366 (2013).

    Article  PubMed  Google Scholar 

  72. Wu, Q. Q. et al. Cathepsin B deficiency attenuates cardiac remodeling in response to pressure overload via TNF-alpha/ASK1/JNK pathway. Am. J. Physiol. Heart Circ. Physiol. 308, H1143–H1154 (2015).

    Article  PubMed  CAS  Google Scholar 

  73. Wu, J. et al. Insights into the activation and inhibition of angiotensin II type 1 receptor in the mechanically loaded heart. Circ. J. 78, 1283–1289 (2014).

    Article  PubMed  CAS  Google Scholar 

  74. Dahl, S. W. et al. Human recombinant pro-dipeptidyl peptidase I (cathepsin C) can be activated by cathepsins L and S but not by autocatalytic processing. Biochemistry 40, 1671–1678 (2001).

    Article  PubMed  CAS  Google Scholar 

  75. Nagler, D. K. et al. Human cathepsin X: A cysteine protease with unique carboxypeptidase activity. Biochemistry 38, 12648–12654 (1999).

    Article  PubMed  CAS  Google Scholar 

  76. Caglic, D., Pungercar, J. R., Pejler, G., Turk, V. & Turk, B. Glycosaminoglycans facilitate procathepsin B activation through disruption of propeptide-mature enzyme interactions. J. Biol. Chem. 282, 33076–33085 (2007).

    Article  PubMed  CAS  Google Scholar 

  77. Reiser, J., Adair, B. & Reinheckel, T. Specialized roles for cysteine cathepsins in health and disease. J. Clin. Invest. 120, 3421–3431 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Hashimoto, Y., Kondo, C. & Katunuma, N. An active 32-kDa cathepsin L is secreted directly from HT 1080 fibrosarcoma cells and not via lysosomal exocytosis. PLoS ONE 10, e0145067 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Rodriguez, A., Webster, P., Ortego, J. & Andrews, N. W. Lysosomes behave as Ca2+-regulated exocytic vesicles in fibroblasts and epithelial cells. J. Cell Biol. 137, 93–104 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Clark, A. K., Wodarski, R., Guida, F., Sasso, O. & Malcangio, M. Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor. Glia 58, 1710–1726 (2010).

    Article  PubMed  Google Scholar 

  81. Yan, D., Wang, H. W., Bowman, R. L. & Joyce, J. A. STAT3 and STAT6 signaling pathways synergize to promote cathepsin secretion from macrophages via IRE1alpha activation. Cell Rep. 16, 2914–2927 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Shi, G. P., Munger, J. S., Meara, J. P., Rich, D. H. & Chapman, H. A. Molecular cloning and expression of human alveolar macrophage cathepsin S, an elastinolytic cysteine protease. J. Biol. Chem. 267, 7258–7262 (1992).

    PubMed  CAS  Google Scholar 

  83. Li, Z., Kienetz, M., Cherney, M. M., James, M. N. & Bromme, D. The crystal and molecular structures of a cathepsin K:chondroitin sulfate complex. J. Mol. Biol. 383, 78–91 (2008).

    Article  PubMed  CAS  Google Scholar 

  84. Novinec, M., Kovacic, L., Lenarcic, B. & Baici, A. Conformational flexibility and allosteric regulation of cathepsin K. Biochem. J. 429, 379–389 (2010).

    Article  PubMed  CAS  Google Scholar 

  85. Almeida, P. C. et al. Cathepsin B activity regulation. Heparin-like glycosaminogylcans protect human cathepsin B from alkaline pH-induced inactivation. J. Biol. Chem. 276, 944–951 (2001).

    Article  PubMed  CAS  Google Scholar 

  86. Turk, B. et al. Human cathepsin B is a metastable enzyme stabilized by specific ionic interactions associated with the active site. Biochemistry 33, 14800–14806 (1994).

    Article  PubMed  CAS  Google Scholar 

  87. Rozhin, J., Sameni, M., Ziegler, G. & Sloane, B. F. Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Res. 54, 6517–6525 (1994).

    PubMed  CAS  Google Scholar 

  88. Reddy, V. Y., Zhang, Q. Y. & Weiss, S. J. Pericellular mobilization of the tissue-destructive cysteine proteinases, cathepsins B, L, and S, by human monocyte-derived macrophages. Proc. Natl Acad. Sci. USA 92, 3849–3853 (1995).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Nanda, A., Gukovskaya, A., Tseng, J. & Grinstein, S. Activation of vacuolar-type proton pumps by protein kinase C. Role in neutrophil pH regulation. J. Biol. Chem. 267, 22740–22746 (1992).

    PubMed  CAS  Google Scholar 

  90. Dames, P. et al. cAMP regulates plasma membrane vacuolar-type H+-ATPase assembly and activity in blowfly salivary glands. Proc. Natl Acad. Sci. USA 103, 3926–3931 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Wang, J. et al. IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe−/− mice. J. Clin. Invest. 121, 3564–3577 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Bynagari-Settipalli, Y. S., Chari, R., Kilpatrick, L. & Kunapuli, S. P. Protein kinase C - possible therapeutic target to treat cardiovascular diseases. Cardiovasc. Hematol. Disord. Drug Targets 10, 292–308 (2010).

    Article  PubMed  CAS  Google Scholar 

  93. Cheng, X. W. et al. Localization of cysteine protease, cathepsin S, to the surface of vascular smooth muscle cells by association with integrin alphanubeta3. Am. J. Pathol. 168, 685–694 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Christ, A., Temmerman, L., Legein, B., Daemen, M. J. & Biessen, E. A. Dendritic cells in cardiovascular diseases: epiphenomenon, contributor, or therapeutic opportunity. Circulation 128, 2603–2613 (2013).

    Article  PubMed  Google Scholar 

  95. Obermajer, N., Svajger, U., Bogyo, M., Jeras, M. & Kos, J. Maturation of dendritic cells depends on proteolytic cleavage by cathepsin X. J. Leukoc. Biol. 84, 1306–1315 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Haerteis, S., Krueger, B., Korbmacher, C. & Rauh, R. The delta-subunit of the epithelial sodium channel (ENaC) enhances channel activity and alters proteolytic ENaC activation. J. Biol. Chem. 284, 29024–29040 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Kos, J., Jevnikar, Z. & Obermajer, N. The role of cathepsin X in cell signaling. Cell Adh. Migr. 3, 164–166 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Sloane, B. F. et al. Cathepsin B: association with plasma membrane in metastatic tumors. Proc. Natl Acad. Sci. USA 83, 2483–2487 (1986).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Mai, J., Finley, R. L. Jr., Waisman, D. M. & Sloane, B. F. Human procathepsin B interacts with the annexin II tetramer on the surface of tumor cells. J. Biol. Chem. 275, 12806–12812 (2000).

    Article  PubMed  CAS  Google Scholar 

  100. Cavallo-Medved, D. et al. Mutant K-ras regulates cathepsin B localization on the surface of human colorectal carcinoma cells. Neoplasia 5, 507–519 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Aits, S. & Jaattela, M. Lysosomal cell death at a glance. J. Cell Sci. 126, 1905–1912 (2013).

    Article  PubMed  CAS  Google Scholar 

  102. Blomgran, R., Zheng, L. & Stendahl, O. Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization. J. Leukoc. Biol. 81, 1213–1223 (2007).

    Article  PubMed  CAS  Google Scholar 

  103. Droga-Mazovec, G. et al. Cysteine cathepsins trigger caspase-dependent cell death through cleavage of bid and antiapoptotic Bcl-2 homologues. J. Biol. Chem. 283, 19140–19150 (2008).

    Article  PubMed  CAS  Google Scholar 

  104. Goulet, B. et al. A cathepsin L isoform that is devoid of a signal peptide localizes to the nucleus in S phase and processes the CDP/Cux transcription factor. Mol. Cell 14, 207–219 (2004).

    Article  PubMed  CAS  Google Scholar 

  105. Truscott, M. et al. CDP/Cux stimulates transcription from the DNA polymerase alpha gene promoter. Mol. Cell. Biol. 23, 3013–3028 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Duncan, E. M. et al. Cathepsin L proteolytically processes histone H3 during mouse embryonic stem cell differentiation. Cell 135, 284–294 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Sansregret, L. et al. The p110 isoform of the CDP/Cux transcription factor accelerates entry into S phase. Mol. Cell. Biol. 26, 2441–2455 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Roberts, L. R. et al. Cathepsin B contributes to bile salt-induced apoptosis of rat hepatocytes. Gastroenterology 113, 1714–1726 (1997).

    Article  PubMed  CAS  Google Scholar 

  109. Prudova, A. et al. TAILS N-terminomics and proteomics show protein degradation dominates over proteolytic processing by cathepsins in pancreatic tumors. Cell Rep. 16, 1762–1773 (2016).

    Article  PubMed  CAS  Google Scholar 

  110. Kasabova, M. et al. Regulation of TGF-beta1-driven differentiation of human lung fibroblasts: emerging roles of cathepsin B and cystatin C. J. Biol. Chem. 289, 16239–16251 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Li, X. et al. Cathepsin B regulates collagen expression by fibroblasts via prolonging TLR2/NF-kappaB activation. Oxid. Med. Cell Longev. 2016, 7894247 (2016).

    PubMed  PubMed Central  Google Scholar 

  112. Authier, F., Metioui, M., Bell, A. W. & Mort, J. S. Negative regulation of epidermal growth factor signaling by selective proteolytic mechanisms in the endosome mediated by cathepsin B. J. Biol. Chem. 274, 33723–33731 (1999).

    Article  PubMed  CAS  Google Scholar 

  113. Glogowska, A. et al. Epidermal growth factor cytoplasmic domain affects ErbB protein degradation by the lysosomal and ubiquitin-proteasome pathway in human cancer cells. Neoplasia 14, 396–409 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Hiwasa, T. et al. Inhibition of cathepsin L-induced degradation of epidermal growth factor receptors by c-Ha-ras gene products. Biochem. Biophys. Res. Commun. 151, 78–85 (1988).

    Article  PubMed  CAS  Google Scholar 

  115. Reinheckel, T. et al. The lysosomal cysteine protease cathepsin L regulates keratinocyte proliferation by control of growth factor recycling. J. Cell Sci. 118, 3387–3395 (2005).

    Article  PubMed  CAS  Google Scholar 

  116. Dennemarker, J. et al. Deficiency for the cysteine protease cathepsin L promotes tumor progressionin mouse epidermis. Oncogene 29, 1611–1621 (2010).

    Article  PubMed  CAS  Google Scholar 

  117. Bianco, R., Melisi, D., Ciardiello, F. & Tortora, G. Key cancer cell signal transduction pathways as therapeutic targets. Eur. J. Cancer 42, 290–294 (2006).

    Article  PubMed  CAS  Google Scholar 

  118. Navab, R. et al. Inhibition of endosomal insulin-like growth factor-I processing by cysteine proteinase inhibitors blocks receptor-mediated functions. J. Biol. Chem. 276, 13644–13649 (2001).

    Article  PubMed  CAS  Google Scholar 

  119. Kraus, S., Fruth, M., Bunsen, T. & Nagler, D. K. IGF-I receptor phosphorylation is impaired in cathepsin X-deficient prostate cancer cells. Biol. Chem. 393, 1457–1462 (2012).

    Article  PubMed  CAS  Google Scholar 

  120. Hafner, A., Obermajer, N. & Kos, J. gamma-Enolase C-terminal peptide promotes cell survival and neurite outgrowth by activation of the PI3K/Akt and MAPK/ERK signalling pathways. Biochem. J. 443, 439–450 (2012).

    Article  PubMed  CAS  Google Scholar 

  121. Berquin, I. M. & Sloane, B. F. Cathepsin B expression in human tumors. Adv. Exp. Med. Biol. 389, 281–294 (1996).

    Article  PubMed  CAS  Google Scholar 

  122. Shi, G. P. et al. Deficiency of the cysteine protease cathepsin S impairs microvessel growth. Circ. Res. 92, 493–500 (2003).

    Article  PubMed  CAS  Google Scholar 

  123. Wang, B. et al. Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors. J. Biol. Chem. 281, 6020–6029 (2006).

    Article  PubMed  CAS  Google Scholar 

  124. Chung, J. H. et al. Cathepsin L derived from skeletal muscle cells transfected with bFGF promotes endothelial cell migration. Exp. Mol. Med. 43, 179–188 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Urbich, C. et al. Cathepsin L is required for endothelial progenitor cell-induced neovascularization. Nat. Med. 11, 206–213 (2005).

    Article  PubMed  CAS  Google Scholar 

  126. Leake, D. S. & Peters, T. J. Proteolytic degradation of low density lipoproteins by arterial smooth muscle cells: the role of individual cathepsins. Biochim. Biophys. Acta 664, 108–116 (1981).

    Article  PubMed  CAS  Google Scholar 

  127. Wong, W. P. et al. Cathepsin B is a novel gender-dependent determinant of cholesterol absorption from the intestine. J. Lipid Res. 54, 816–822 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Lutgens, S. P. et al. Gene profiling of cathepsin K deficiency in atherogenesis: profibrotic but lipogenic. J. Pathol. 210, 334–343 (2006).

    Article  PubMed  CAS  Google Scholar 

  129. Olofsson, S. O. & Boren, J. Apolipoprotein B: a clinically important apolipoprotein which assembles atherogenic lipoproteins and promotes the development of atherosclerosis. J. Intern. Med. 258, 395–410 (2005).

    Article  PubMed  CAS  Google Scholar 

  130. Linke, M. et al. Degradation of apolipoprotein B-100 by lysosomal cysteine cathepsins. Biol. Chem. 387, 1295–1303 (2006).

    Article  PubMed  CAS  Google Scholar 

  131. Han, S. R. et al. Enzymatically modified LDL induces cathepsin H in human monocytes: potential relevance in early atherogenesis. Arterioscler. Thromb. Vasc. Biol. 23, 661–667 (2003).

    Article  PubMed  CAS  Google Scholar 

  132. Qin, Y. & Shi, G. P. Cysteinyl cathepsins and mast cell proteases in the pathogenesis and therapeutics of cardiovascular diseases. Pharmacol. Ther. 131, 338–350 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Lindstedt, L., Lee, M., Oorni, K., Bromme, D. & Kovanen, P. T. Cathepsins F and S block HDL3-induced cholesterol efflux from macrophage foam cells. Biochem. Biophys. Res. Commun. 312, 1019–1024 (2003).

    Article  PubMed  CAS  Google Scholar 

  134. Burns-Kurtis, C. L. et al. Cathepsin S expression is up-regulated following balloon angioplasty in the hypercholesterolemic rabbit. Cardiovasc. Res. 62, 610–620 (2004).

    Article  PubMed  CAS  Google Scholar 

  135. Sun, Y. et al. Free cholesterol accumulation in macrophage membranes activates Toll-like receptors and p38 mitogen-activated protein kinase and induces cathepsin K. Circ. Res. 104, 455–465 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Li, W., Yuan, X. M., Olsson, A. G. & Brunk, U. T. Uptake of oxidized LDL by macrophages results in partial lysosomal enzyme inactivation and relocation. Arterioscler. Thromb. Vasc. Biol. 18, 177–184 (1998).

    Article  PubMed  CAS  Google Scholar 

  137. Li, W. & Yuan, X. M. Increased expression and translocation of lysosomal cathepsins contribute to macrophage apoptosis in atherogenesis. Ann. NY Acad. Sci. 1030, 427–433 (2004).

    Article  PubMed  CAS  Google Scholar 

  138. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Fonovic, U. P., Jevnikar, Z. & Kos, J. Cathepsin S generates soluble CX3CL1 (fractalkine) in vascular smooth muscle cells. Biol. Chem. 394, 1349–1352 (2013).

    Article  PubMed  CAS  Google Scholar 

  140. Pagano, M. B. et al. Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms. Proc. Natl Acad. Sci. USA 104, 2855–2860 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Akk, A. M. et al. Dipeptidyl peptidase I-dependent neutrophil recruitment modulates the inflammatory response to Sendai virus infection. J. Immunol. 180, 3535–3542 (2008).

    Article  PubMed  CAS  Google Scholar 

  142. Obermajer, N., Premzl, A., Zavasnik Bergant, T., Turk, B. & Kos, J. Carboxypeptidase cathepsin X mediates beta2-integrin-dependent adhesion of differentiated U-937 cells. Exp. Cell Res. 312, 2515–2527 (2006).

    Article  PubMed  CAS  Google Scholar 

  143. Lechner, A. M. et al. RGD-dependent binding of procathepsin X to integrin alphavbeta3 mediates cell-adhesive properties. J. Biol. Chem. 281, 39588–39597 (2006).

    Article  PubMed  CAS  Google Scholar 

  144. Jevnikar, Z. et al. Cathepsin X cleavage of the beta2 integrin regulates talin-binding and LFA-1 affinity in T cells. J. Leukoc. Biol. 90, 99–109 (2011).

    Article  PubMed  CAS  Google Scholar 

  145. Jevnikar, Z., Obermajer, N. & Kos, J. LFA-1 fine-tuning by cathepsin X. IUBMB Life 63, 686–693 (2011).

    PubMed  CAS  Google Scholar 

  146. Chwieralski, C. E., Welte, T. & Buhling, F. Cathepsin-regulated apoptosis. Apoptosis 11, 143–149 (2006).

    Article  PubMed  CAS  Google Scholar 

  147. Saelens, X. et al. Toxic proteins released from mitochondria in cell death. Oncogene 23, 2861–2874 (2004).

    Article  PubMed  CAS  Google Scholar 

  148. Ben-Ari, Z. et al. Cathepsin B inactivation attenuates the apoptotic injury induced by ischemia/reperfusion of mouse liver. Apoptosis 10, 1261–1269 (2005).

    Article  PubMed  CAS  Google Scholar 

  149. Kilinc, M. et al. Lysosomal rupture, necroapoptotic interactions and potential crosstalk between cysteine proteases in neurons shortly after focal ischemia. Neurobiol. Dis. 40, 293–302 (2010).

    Article  PubMed  CAS  Google Scholar 

  150. Cheriyath, V., Kuhns, M. A., Kalaycio, M. E. & Borden, E. C. Potentiation of apoptosis by histone deacetylase inhibitors and doxorubicin combination: cytoplasmic cathepsin B as a mediator of apoptosis in multiple myeloma. Br. J. Cancer 104, 957–967 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Xie, L. et al. Cystatin C increases in cardiac injury: a role in extracellular matrix protein modulation. Cardiovasc. Res. 87, 628–635 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Hsu, S. F., Hsu, C. C., Cheng, B. C. & Lin, C. H. Cathepsin B is involved in the heat shock induced cardiomyocytes apoptosis as well as the anti-apoptosis effect of HSP-70. Apoptosis 19, 1571–1580 (2014).

    Article  PubMed  CAS  Google Scholar 

  153. Byrne, S. M. et al. Cathepsin B controls the persistence of memory CD8 + T lymphocytes. J. Immunol. 189, 1133–1143 (2012).

    Article  PubMed  CAS  Google Scholar 

  154. Wei, D. H. et al. Cathepsin L stimulates autophagy and inhibits apoptosis of ox-LDL-induced endothelial cells: potential role in atherosclerosis. Int. J. Mol. Med. 31, 400–406 (2013).

    Article  PubMed  CAS  Google Scholar 

  155. Yu, W. et al. Cystatin C deficiency promotes epidermal dysplasia in K14-HPV16 transgenic mice. PLoS ONE 5, e13973 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Ohashi, K., Naruto, M., Nakaki, T. & Sano, E. Identification of interleukin-8 converting enzyme as cathepsin L. Biochim. Biophys. Acta 1649, 30–39 (2003).

    Article  PubMed  CAS  Google Scholar 

  157. Ha, S. D. et al. Cathepsin B is involved in the trafficking of TNF-alpha-containing vesicles to the plasma membrane in macrophages. J. Immunol. 181, 690–697 (2008).

    Article  PubMed  CAS  Google Scholar 

  158. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    Article  PubMed  CAS  Google Scholar 

  159. Ridker, P. M. et al. Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 390, 1833–1842 (2017).

    Article  PubMed  CAS  Google Scholar 

  160. Niemi, K. et al. Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. J. Immunol. 186, 6119–6128 (2011).

    Article  PubMed  CAS  Google Scholar 

  161. Wang, W. L. et al. Enhancement of endothelial permeability by free fatty acid through lysosomal cathepsin B-mediated Nlrp3 inflammasome activation. Oncotarget 7, 73229–73241 (2016).

    PubMed  PubMed Central  Google Scholar 

  162. Murphy, N., Grehan, B. & Lynch, M. A. Glial uptake of amyloid beta induces NLRP3 inflammasome formation via cathepsin-dependent degradation of NLRP10. Neuromolecular Med. 16, 205–215 (2014).

    Article  PubMed  CAS  Google Scholar 

  163. Orlowski, G. M. et al. Multiple cathepsins promote pro-IL-1beta synthesis and NLRP3-mediated IL-1beta activation. J. Immunol. 195, 1685–1697 (2015).

    Article  PubMed  CAS  Google Scholar 

  164. Hao, L. et al. Odanacatib, a cathepsin K-specific inhibitor, inhibits inflammation and bone loss caused by periodontal diseases. J. Periodontol. 86, 972–983 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Tabas, I. & Lichtman, A. H. Monocyte-macrophages and T cells in atherosclerosis. Immunity 47, 621–634 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  166. Chistiakov, D. A., Orekhov, A. N. & Bobryshev, Y. V. Immune-inflammatory responses in atherosclerosis: Role of an adaptive immunity mainly driven by T and B cells. Immunobiology 221, 1014–1033 (2016).

    Article  PubMed  CAS  Google Scholar 

  167. Tolosa, E. et al. Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis. J. Clin. Invest. 112, 517–526 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Puente, X. S., Sanchez, L. M., Overall, C. M. & Lopez-Otin, C. Human and mouse proteases: a comparative genomic approach. Nat. Rev. Genet. 4, 544–558 (2003).

    Article  PubMed  CAS  Google Scholar 

  169. Santamaria, I. et al. Cathepsin L2, a novel human cysteine proteinase produced by breast and colorectal carcinomas. Cancer Res. 58, 1624–1630 (1998).

    PubMed  CAS  Google Scholar 

  170. Joseph, L. J., Chang, L. C., Stamenkovich, D. & Sukhatme, V. P. Complete nucleotide and deduced amino acid sequences of human and murine preprocathepsin L. An abundant transcript induced by transformation of fibroblasts. J. Clin. Invest. 81, 1621–1629 (1988).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Benavides, F. et al. The CD4 T cell-deficient mouse mutation nackt (nkt) involves a deletion in the cathepsin L (CtsI) gene. Immunogenetics 53, 233–242 (2001).

    Article  PubMed  CAS  Google Scholar 

  172. Sevenich, L. et al. Expression of human cathepsin L or human cathepsin V in mouse thymus mediates positive selection of T helper cells in cathepsin L knock-out mice. Biochimie 92, 1674–1680 (2010).

    Article  PubMed  CAS  Google Scholar 

  173. Yamada, A., Ishimaru, N., Arakaki, R., Katunuma, N. & Hayashi, Y. Cathepsin L inhibition prevents murine autoimmune diabetes via suppression of CD8(+) T cell activity. PLoS ONE 5, e12894 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Maekawa, Y. et al. Switch of CD4 + T cell differentiation from Th2 to Th1 by treatment with cathepsin B inhibitor in experimental leishmaniasis. J. Immunol. 161, 2120–2127 (1998).

    PubMed  CAS  Google Scholar 

  175. Zhang, T. et al. Treatment with cathepsin L inhibitor potentiates Th2-type immune response in Leishmania major-infected BALB/c mice. Int. Immunol. 13, 975–982 (2001).

    Article  PubMed  CAS  Google Scholar 

  176. Gonzalez-Leal, I. J. et al. Cathepsin B in antigen-presenting cells controls mediators of the Th1 immune response during Leishmania major infection. PLoS Negl. Trop. Dis. 8, e3194 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Badano, M. N. et al. B-Cell lymphopoiesis is regulated by cathepsin L. PLoS ONE 8, e61347 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Riese, R. J. et al. Cathepsin S activity regulates antigen presentation and immunity. J. Clin. Invest. 101, 2351–2363 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Kitamura, H. et al. IL-6-STAT3 controls intracellular MHC class II alphabeta dimer level through cathepsin S activity in dendritic cells. Immunity 23, 491–502 (2005).

    Article  PubMed  CAS  Google Scholar 

  180. Guo, X. & Dhodapkar, K. M. Central and overlapping role of Cathepsin B and inflammasome adaptor ASC in antigen presenting function of human dendritic cells. Hum. Immunol. 73, 871–878 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Skeoch, S. & Bruce, I. N. Atherosclerosis in rheumatoid arthritis: is it all about inflammation? Nat. Rev. Rheumatol. 11, 390–400 (2015).

    Article  PubMed  CAS  Google Scholar 

  182. Kurata, A. et al. Aortic aneurysms in systemic lupus erythematosus: a meta-analysis of 35 cases in the literature and two different pathogeneses. Cardiovasc. Pathol. 20, e1–e7 (2011).

    Article  PubMed  Google Scholar 

  183. Shovman, O. et al. Aortic aneurysm associated with rheumatoid arthritis: a population-based cross-sectional study. Clin. Rheumatol 35, 2657–2661 (2016).

    Article  PubMed  Google Scholar 

  184. Anania, C. et al. Increased prevalence of vulnerable atherosclerotic plaques and low levels of natural IgM antibodies against phosphorylcholine in patients with systemic lupus erythematosus. Arthritis Res. Ther. 12, R214 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Ma, Z. et al. Accelerated atherosclerosis in ApoE deficient lupus mouse models. Clin. Immunol. 127, 168–175 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Rose, S. et al. A novel mouse model that develops spontaneous arthritis and is predisposed towards atherosclerosis. Ann. Rheum. Dis. 72, 89–95 (2013).

    Article  PubMed  Google Scholar 

  187. Ruge, T., Sodergren, A., Wallberg-Jonsson, S., Larsson, A. & Arnlov, J. Circulating plasma levels of cathepsin S and L are not associated with disease severity in patients with rheumatoid arthritis. Scand. J. Rheumatol. 43, 371–373 (2014).

    Article  PubMed  CAS  Google Scholar 

  188. Pozgan, U. et al. Expression and activity profiling of selected cysteine cathepsins and matrix metalloproteinases in synovial fluids from patients with rheumatoid arthritis and osteoarthritis. Biol. Chem. 391, 571–579 (2010).

    Article  PubMed  CAS  Google Scholar 

  189. Haves-Zburof, D. et al. Cathepsins and their endogenous inhibitors cystatins: expression and modulation in multiple sclerosis. J. Cell. Mol. Med. 15, 2421–2429 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Allan, E. R. & Yates, R. M. Redundancy between cysteine cathepsins in murine experimental autoimmune encephalomyelitis. PLoS ONE 10, e0128945 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Asagiri, M. et al. Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science 319, 624–627 (2008).

    Article  PubMed  CAS  Google Scholar 

  192. Rupanagudi, K. V. et al. Cathepsin S inhibition suppresses systemic lupus erythematosus and lupus nephritis because cathepsin S is essential for MHC class II-mediated CD4 T cell and B cell priming. Ann. Rheum. Dis. 74, 452–463 (2015).

    Article  PubMed  CAS  Google Scholar 

  193. Scheinecker, C., Bonelli, M. & Smolen, J. S. Pathogenetic aspects of systemic lupus erythematosus with an emphasis on regulatory T cells. J. Autoimmun. 35, 269–275 (2010).

    Article  PubMed  CAS  Google Scholar 

  194. Celhar, T., Magalhaes, R. & Fairhurst, A. M. TLR7 and TLR9 in SLE: when sensing self goes wrong. Immunol. Res. 53, 58–77 (2012).

    Article  PubMed  CAS  Google Scholar 

  195. Tamosiuniene, R. & Nicolls, M. R. Regulatory T cells and pulmonary hypertension. Trends Cardiovasc. Med. 21, 166–171 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  196. Yodoi, K. et al. Foxp3 + regulatory T cells play a protective role in angiotensin II-induced aortic aneurysm formation in mice. Hypertension 65, 889–895 (2015).

    Article  PubMed  CAS  Google Scholar 

  197. Zhao, G. et al. Increased circulating cathepsin K in patients with chronic heart failure. PLoS ONE 10, e0136093 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Mirjanic-Azaric, B. et al. Interrelated cathepsin S-lowering and LDL subclass profile improvements induced by atorvastatin in the plasma of stable angina patients. J. Atheroscler. Thromb. 21, 868–877 (2014).

    Article  PubMed  CAS  Google Scholar 

  199. Cheng, X. W. et al. Circulating cathepsin K as a potential novel biomarker of coronary artery disease. Atherosclerosis 228, 211–216 (2013).

    Article  PubMed  CAS  Google Scholar 

  200. Fujita, M. et al. Mechanisms with clinical implications for atrial fibrillation-associated remodeling: cathepsin K expression, regulation, and therapeutic target and biomarker. J. Am. Heart Assoc. 2, e000503 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Shalia, K. K., Mashru, M. R., Shah, V. K., Soneji, S. L. & Payannavar, S. Levels of cathepsins in acute myocardial infarction. Indian Heart J. 64, 290–294 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Zhang, J. et al. Plasma cathepsin L and its related pro/antiangiogenic factors play useful roles in predicting rich coronary collaterals in patients with coronary heart disease. J. Int. Med. Res. 38, 1389–1403 (2010).

    Article  PubMed  CAS  Google Scholar 

  203. Izumi, Y. et al. Impact of circulating cathepsin K on the coronary calcification and the clinical outcome in chronic kidney disease patients. Heart Vessels 31, 6–14 (2016).

    Article  PubMed  Google Scholar 

  204. Qin, Y. et al. Combined Cathepsin S and hs-CRP predicting inflammation of abdominal aortic aneurysm. Clin. Biochem. 46, 1026–1029 (2013).

    Article  PubMed  CAS  Google Scholar 

  205. Jobs, E. et al. Association between serum cathepsin S and mortality in older adults. JAMA 306, 1113–1121 (2011).

    Article  PubMed  CAS  Google Scholar 

  206. Feldreich, T. et al. The association between serum cathepsin L and mortality in older adults. Atherosclerosis 254, 109–116 (2016).

    Article  PubMed  CAS  Google Scholar 

  207. Kramer, L., Turk, D. & Turk, B. The future of cysteine cathepsins in disease management. Trends Pharmacol. Sci. 38, 873–898 (2017).

    Article  PubMed  CAS  Google Scholar 

  208. Li, C. S. et al. Identification of a potent and selective non-basic cathepsin K inhibitor. Bioorg. Med. Chem. Lett. 16, 1985–1989 (2006).

    Article  PubMed  CAS  Google Scholar 

  209. Gauthier, J. Y. et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 18, 923–928 (2008).

    Article  PubMed  CAS  Google Scholar 

  210. Stoch, S. A. & Wagner, J. A. Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin. Pharmacol. Ther. 83, 172–176 (2008).

    Article  PubMed  CAS  Google Scholar 

  211. Bone, H. G. et al. Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial. Osteoporos Int. 26, 699–712 (2015).

    Article  PubMed  CAS  Google Scholar 

  212. Mullard, A. Merck & Co. drops osteoporosis drug odanacatib. Nat. Rev. Drug Discov. 15, 669 (2016).

    PubMed  PubMed Central  Google Scholar 

  213. Le Gall, C., Bonnelye, E. & Clezardin, P. Cathepsin K inhibitors as treatment of bone metastasis. Curr. Opin. Support Palliat. Care 2, 218–222 (2008).

    Article  PubMed  Google Scholar 

  214. Black, W. C. & Percival, M. D. The consequences of lysosomotropism on the design of selective cathepsin K inhibitors. Chembiochem 7, 1525–1535 (2006).

    Article  PubMed  CAS  Google Scholar 

  215. Engelke, K. et al. The effect of the cathepsin K inhibitor ONO-5334 on trabecular and cortical bone in postmenopausal osteoporosis: the OCEAN study. J. Bone Miner. Res. 29, 629–638 (2014).

    Article  PubMed  CAS  Google Scholar 

  216. Eastell, R. et al. Morning versus evening dosing of the cathepsin K inhibitor ONO-5334: effects on bone resorption in postmenopausal women in a randomized, phase 1 trial. Osteoporos. Int. 27, 309–318 (2016).

    Article  PubMed  CAS  Google Scholar 

  217. Tanaka, M., Hashimoto, Y. & Hasegawa, C. An oral cathepsin K inhibitor ONO-5334 inhibits N-terminal and C-terminal collagen crosslinks in serum and urine at similar plasma concentrations in postmenopausal women. Bone 81, 178–185 (2015).

    Article  PubMed  CAS  Google Scholar 

  218. Nagase, S. et al. Bone turnover markers and pharmacokinetics of a new sustained-release formulation of the cathepsin K inhibitor, ONO-5334, in healthy post-menopausal women. J. Bone Miner. Metab. 33, 93–100 (2015).

    Article  PubMed  CAS  Google Scholar 

  219. Stellos, K. et al. Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation. Nat. Med. 22, 1140–1150 (2016).

    Article  PubMed  CAS  Google Scholar 

  220. Wulff, B. E., Sakurai, M. & Nishikura, K. Elucidating the inosinome: global approaches to adenosine-to-inosine RNA editing. Nat. Rev. Genet. 12, 81–85 (2011).

    Article  PubMed  CAS  Google Scholar 

  221. Eggington, J. M., Greene, T. & Bass, B. L. Predicting sites of ADAR editing in double-stranded RNA. Nat. Commun. 2, 319 (2011).

    Article  PubMed  CAS  Google Scholar 

  222. Bass, B. L. et al. A standardized nomenclature for adenosine deaminases that act on RNA. RNA 3, 947–949 (1997).

    PubMed  PubMed Central  CAS  Google Scholar 

  223. Kim, D. D. et al. Widespread RNA editing of embedded alu elements in the human transcriptome. Genome Res. 14, 1719–1725 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. Athanasiadis, A., Rich, A. & Maas, S. Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol. 2, e391 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  225. Folkersen, L. et al. Unraveling divergent gene expression profiles in bicuspid and tricuspid aortic valve patients with thoracic aortic dilatation: the ASAP study. Mol. Med. 17, 1365–1373 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  226. Lemaire, P. A. et al. Chondroitin sulfate promotes activation of cathepsin K. J. Biol. Chem. 289, 21562–21572 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  227. Karangelis, D. E. et al. Glycosaminoglycans as key molecules in atherosclerosis: the role of versican and hyaluronan. Curr. Med. Chem. 17, 4018–4026 (2010).

    Article  PubMed  CAS  Google Scholar 

  228. Li, Z., Hou, W. S. & Bromme, D. Collagenolytic activity of cathepsin K is specifically modulated by cartilage-resident chondroitin sulfates. Biochemistry 39, 529–536 (2000).

    Article  PubMed  CAS  Google Scholar 

  229. Li, Z. et al. Regulation of collagenase activities of human cathepsins by glycosaminoglycans. J. Biol. Chem. 279, 5470–5479 (2004).

    Article  PubMed  CAS  Google Scholar 

  230. Buck, M. R., Karustis, D. G., Day, N. A., Honn, K. V. & Sloane, B. F. Degradation of extracellular-matrix proteins by human cathepsin B from normal and tumour tissues. Biochem. J. 282, 273–278 (1992).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  231. Friedrichs, B. et al. Thyroid functions of mouse cathepsins B, K, and L. J. Clin. Invest. 111, 1733–1745 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  232. Brix, K., Linke, M., Tepel, C. & Herzog, V. Cysteine proteinases mediate extracellular prohormone processing in the thyroid. Biol. Chem. 382, 717–725 (2001).

    PubMed  CAS  Google Scholar 

  233. Garnero, P. et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J. Biol. Chem. 273, 32347–32352 (1998).

    Article  PubMed  CAS  Google Scholar 

  234. Bromme, D., Okamoto, K., Wang, B. B. & Biroc, S. Human cathepsin O2, a matrix protein-degrading cysteine protease expressed in osteoclasts. Functional expression of human cathepsin O2 in Spodoptera frugiperda and characterization of the enzyme. J. Biol. Chem. 271, 2126–2132 (1996).

    Article  PubMed  CAS  Google Scholar 

  235. Ishidoh, K. & Kominami, E. Procathepsin L degrades extracellular matrix proteins in the presence of glycosaminoglycans in vitro. Biochem. Biophys. Res. Commun. 217, 624–631 (1995).

    Article  PubMed  CAS  Google Scholar 

  236. Maciewicz, R. A. & Etherington, D. J. A comparison of four cathepsins (B, L, N and S) with collagenolytic activity from rabbit spleen. Biochem. J. 256, 433–440 (1988).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  237. Felbor, U. et al. Secreted cathepsin L generates endostatin from collagen XVIII. EMBO J. 19, 1187–1194 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  238. Veillard, F. et al. Cysteine cathepsins S and L modulate anti-angiogenic activities of human endostatin. J. Biol. Chem. 286, 37158–37167 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  239. Du, X., Chen, N. L., Wong, A., Craik, C. S. & Bromme, D. Elastin degradation by cathepsin V requires two exosites. J. Biol. Chem. 288, 34871–34881 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  240. Hall, A. et al. Structural basis for different inhibitory specificities of human cystatins C and D. Biochemistry 37, 4071–4079 (1998).

    Article  PubMed  CAS  Google Scholar 

  241. Taleb, S., Cancello, R., Clement, K. & Lacasa, D. Cathepsin s promotes human preadipocyte differentiation: possible involvement of fibronectin degradation. Endocrinology 147, 4950–4959 (2006).

    Article  PubMed  CAS  Google Scholar 

  242. Platt, M. O., Ankeny, R. F. & Jo, H. Laminar shear stress inhibits cathepsin L activity in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 26, 1784–1790 (2006).

    Article  PubMed  CAS  Google Scholar 

  243. Urbich, C., Dernbach, E., Rossig, L., Zeiher, A. M. & Dimmeler, S. High glucose reduces cathepsin L activity and impairs invasion of circulating progenitor cells. J. Mol. Cell Cardiol. 45, 429–436 (2008).

    Article  PubMed  CAS  Google Scholar 

  244. Kaakinen, R., Lindstedt, K. A., Sneck, M., Kovanen, P. T. & Oorni, K. Angiotensin II increases expression and secretion of cathepsin F in cultured human monocyte-derived macrophages: an angiotensin II type 2 receptor-mediated effect. Atherosclerosis 192, 323–327 (2007).

    Article  PubMed  CAS  Google Scholar 

  245. Castellano, J., Badimon, L. & Llorente-Cortes, V. Amyloid-beta increases metallo- and cysteine protease activities in human macrophages. J. Vasc. Res. 51, 58–67 (2014).

    Article  PubMed  CAS  Google Scholar 

  246. Lugering, N. et al. IL-10 synergizes with IL-4 and IL-13 in inhibiting lysosomal enzyme secretion by human monocytes and lamina propria mononuclear cells from patients with inflammatory bowel disease. Dig. Dis. Sci. 43, 706–714 (1998).

    Article  PubMed  CAS  Google Scholar 

  247. Akenhead, M. L., Fukuda, S., Schmid-Schonbein, G. W. & Shin, H. Y. Fluid shear-induced cathepsin B release in the control of Mac1-dependent neutrophil adhesion. J. Leukoc. Biol. 102, 117–126 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank C. Swallom (Brigham and Women’s Hospital, Boston, MA, USA) for editorial assistance. The authors are supported by grants from the AHA (17POST33670564 to C.-L.L.), the National Natural Science Foundation of China (81460042 and 81770487 to J.G.), the US National Institutes of Health (HL080472 to P.L. and HL123568 and HL60942 to G.-P.S.), and the Robert R. McCormick Charitable Fund (P.L.).

Author information

Author notes

  1. These authors contributed equally: Cong-Lin Liu, Junli Guo

Authors and Affiliations

  1. Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Cong-Lin Liu & Guo-Ping Shi

  2. Institute of Cardiovascular Research, the First Affiliated Hospital, Emergency and Trauma College, Hainan Medical University, Haikou, China

    Junli Guo & Guo-Ping Shi

  3. Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Cong-Lin Liu, Junli Guo, Xian Zhang, Galina K. Sukhova, Peter Libby & Guo-Ping Shi

Authors
  1. Cong-Lin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junli Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Galina K. Sukhova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Libby
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guo-Ping Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.-L.L., J.G., X.Z., G.K.S., and G.-P.S. researched the data for the article. C.-L.L., J.G., P.L., and G.-P.S. provided substantial contribution to discussions of the content. P.L. and G.-P.S. wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Guo-Ping Shi.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Predomain

A short signal peptide located at the amino-terminal domain of cathepsin precursors that is removed during intracellular trafficking.

Prodomain

An amino-terminal peptide of cathepsin precursors that is removed during cathepsin maturation and activation.

M2 macrophages

Alternatively activated macrophages characterized by the production of high levels of anti-inflammatory cytokines.

Buried fibrous caps

Fibrous caps that are unstable and prone to rupture.

Neointima

A new or thickened layer of arterial intima formed in the aorta by migration and proliferation of cells from the media.

M1 macrophages

Classically activated macrophages characterized by the production of high levels of pro-inflammatory cytokines.

Fractional shortening

The fraction of any diastolic dimension that is lost in systole, which is used as measure of cardiac function.

Morphea

A skin condition that causes painless and discoloured patches.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, CL., Guo, J., Zhang, X. et al. Cysteine protease cathepsins in cardiovascular disease: from basic research to clinical trials. Nat Rev Cardiol 15, 351–370 (2018). https://doi.org/10.1038/s41569-018-0002-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-018-0002-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research