Yonsei Med J.  2014 Jul;55(4):912-919. 10.3349/ymj.2014.55.4.912.

Increased Serum Cathepsin K in Patients with Coronary Artery Disease

• Li X
• Li Y
• Jin J
• Jin D
• Cui L
• Li X
• Rei Y
• Jiang H
• Zhao G
• Yang G
• Zhu E
• Nan Y
• Cheng X

• KMID: 2130814
• DOI: http://doi.org/10.3349/ymj.2014.55.4.912

Abstract

PURPOSE
Cathepsin K is a potent collagenase implicated in human and animal atherosclerosis-based vascular remodeling. This study examined the hypothesis that serum CatK is associated with the prevalence of coronary artery disease (CAD).
MATERIALS AND METHODS
Between January 2011 and December 2012, 256 consecutive subjects were enrolled from among patients who underwent coronary angiography and percutaneous coronary intervention treatment. A total of 129 age-matched subjects served as controls.
RESULTS
The subjects' serum cathepsin K and high sensitive C-reactive protein (hs-CRP) and high-density lipoprotein cholesterol were measured. The patients with CAD had significantly higher serum cathepsin K levels compared to the controls (130.8+/-25.5 ng/mL vs. 86.9+/-25.5 ng/mL, p<0.001), and the patients with acute coronary syndrome had significantly higher serum cathepsin K levels compared to those with stable angina pectoris (137.1+/-26.9 ng/mL vs. 102.6+/-12.9 ng/mL, p<0.001). A linear regression analysis showed that overall, the cathepsin K levels were inversely correlated with the high-density lipoprotein levels (r=-0.29, p<0.01) and positively with hs-CRP levels (r=0.32, p<0.01). Multiple logistic regression analyses shows that cathepsin K levels were independent predictors of CAD (odds ratio, 1.76; 95% confidence interval, 1.12 to 1.56; p<0.01).
CONCLUSION
These data indicated that elevated levels of cathepsin K are closely associated with the presence of CAD and that circulating cathepsin K serves a useful biomarker for CAD.

Keyword

Cathepsin K; coronary artery disease; biomarker; high sensitive C-reactive protein; myocardial ischemia

MeSH Terms

Aged
Biological Markers/blood
C-Reactive Protein/metabolism
Cathepsin K/*blood
Coronary Artery Disease/*blood/metabolism
Female
Humans
Male
Middle Aged
Biological Markers
C-Reactive Protein
Cathepsin K

Reference

1. Turk V, Turk B, Turk D. Lysosomal cysteine proteases: facts and opportunities. EMBO J. 2001; 20:4629–4633.

2. Cheng XW, Shi GP, Kuzuya M, Sasaki T, Okumura K, Murohara T. Role for cysteine protease cathepsins in heart disease: focus on biology and mechanisms with clinical implication. Circulation. 2012; 125:1551–1562.

3. Cheng XW, Huang Z, Kuzuya M, Okumura K, Murohara T. Cysteine protease cathepsins in atherosclerosis-based vascular disease and its complications. Hypertension. 2011; 58:978–986.

4. Reiser J, Adair B, Reinheckel T. Specialized roles for cysteine cathepsins in health and disease. J Clin Invest. 2010; 120:3421–3431.

5. Sukhova GK, Shi GP, Simon DI, Chapman HA, 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. 1998; 102:576–583.

6. Shi GP, Sukhova GK, Grubb A, Ducharme A, Rhode LH, Lee RT, et al. Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J Clin Invest. 1999; 104:1191–1197.

7. Cheng XW, Kuzuya M, Sasaki T, Arakawa K, Kanda S, Sumi D, et al. Increased expression of elastolytic cysteine proteases, cathepsins S and K, in the neointima of balloon-injured rat carotid arteries. Am J Pathol. 2004; 164:243–251.

8. Burns-Kurtis CL, Olzinski AR, Needle S, Fox JH, Capper EA, Kelly FM, et al. Cathepsin S expression is up-regulated following balloon angioplasty in the hypercholesterolemic rabbit. Cardiovasc Res. 2004; 62:610–620.

9. Sun M, Chen M, Liu Y, Fukuoka M, Zhou K, Li G, et al. Cathepsin-L contributes to cardiac repair and remodelling post-infarction. Cardiovasc Res. 2011; 89:374–383.

10. Sun J, Sukhova GK, Zhang J, Chen H, Sjöberg S, Libby P, et al. Cathepsin L activity is essential to elastase perfusion-induced abdominal aortic aneurysms in mice. Arterioscler Thromb Vasc Biol. 2011; 31:2500–2508.

11. Sun J, Sukhova GK, Zhang J, Chen H, Sjöberg S, Libby P, et al. Cathepsin K deficiency reduces elastase perfusion-induced abdominal aortic aneurysms in mice. Arterioscler Thromb Vasc Biol. 2012; 32:15–23.

12. Cheng XW, Murohara T, Kuzuya M, Izawa H, Sasaki T, Obata K, et al. Superoxide-dependent cathepsin activation is associated with hypertensive myocardial remodeling and represents a target for angiotensin II type 1 receptor blocker treatment. Am J Pathol. 2008; 173:358–369.

13. Li Z, Hou WS, Brömme D. Collagenolytic activity of cathepsin K is specifically modulated by cartilage-resident chondroitin sulfates. Biochemistry. 2000; 39:529–536.

14. Novinec M, Grass RN, Stark WJ, Turk V, Baici A, Lenarcic B. Interaction between human cathepsins K, L, and S and elastins: mechanism of elastinolysis and inhibition by macromolecular inhibitors. J Biol Chem. 2007; 282:7893–7902.

15. Liu J, Sukhova GK, Yang JT, Sun J, Ma L, Ren A, et al. Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis, and vascular cells. Atherosclerosis. 2006; 184:302–311.

16. Cheng XW, Kuzuya M, Nakamura K, Di Q, Liu Z, Sasaki T, et al. Localization of cysteine protease, cathepsin S, to the surface of vascular smooth muscle cells by association with integrin alphanubeta3. Am J Pathol. 2006; 168:685–694.

17. Lutgens SP, Cleutjens KB, Daemen MJ, Heeneman S. Cathepsin cysteine proteases in cardiovascular disease. FASEB J. 2007; 21:3029–3041.

18. Lutgens E, Lutgens SP, Faber BC, Heeneman S, Gijbels MM, de Winther MP, et al. Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation. Circulation. 2006; 113:98–107.

19. Hua Y, Xu X, Shi GP, Chicco AJ, Ren J, Nair S. Cathepsin K knockout alleviates pressure overload-induced cardiac hypertrophy. Hypertension. 2013; 61:1184–1192.

20. Hua Y, Zhang Y, Dolence J, Shi GP, Ren J, Nair S. Cathepsin K knockout mitigates high-fat diet-induced cardiac hypertrophy and contractile dysfunction. Diabetes. 2013; 62:498–509.

21. Cheng XW, Obata K, Kuzuya M, Izawa H, Nakamura K, Asai E, et al. Elastolytic cathepsin induction/activation system exists in myocardium and is upregulated in hypertensive heart failure. Hypertension. 2006; 48:979–987.

22. Smith ER, Tomlinson LA, Ford ML, McMahon LP, Rajkumar C, Holt SG. Elastin degradation is associated with progressive aortic stiffening and all-cause mortality in predialysis chronic kidney disease. Hypertension. 2012; 59:973–978.

23. Liu J, Ma L, Yang J, Ren A, Sun Z, Yan G, et al. Increased serum cathepsin S in patients with atherosclerosis and diabetes. Atherosclerosis. 2006; 186:411–419.

24. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. Eur Heart J. 2012; 33:2551–2567.

25. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, et al. American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2001; 37:1478–1492.

26. Libby P. Mechanisms of acute coronary syndromes. N Engl J Med. 2013; 369:883–884.

27. Libby P, Lichtman AH, Hansson GK. Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity. 2013; 38:1092–1104.

28. Li X, Liu Z, Cheng Z, Cheng X. Cysteinyl cathepsins: multifunctional enzymes in cardiovascular disease. Chonnam Med J. 2012; 48:77–85.

29. Zografos TA, Haliassos A, Korovesis S, Giazitzoglou E, Serelis J, Katritsis DG. Serum cathepsin levels in coronary artery ectasia. Int J Cardiol. 2010; 145:606–607.

30. Liu Y, Li X, Peng D, Tan Z, Liu H, Qing Y, et al. Usefulness of serum cathepsin L as an independent biomarker in patients with coronary heart disease. Am J Cardiol. 2009; 103:476–481.

31. Chatzizisis YS, Baker AB, Sukhova GK, Koskinas KC, Papafaklis MI, Beigel R, et al. Augmented expression and activity of extracellular matrix-degrading enzymes in regions of low endothelial shear stress colocalize with coronary atheromata with thin fibrous caps in pigs. Circulation. 2011; 123:621–630.

32. Platt MO, Ankeny RF, Shi GP, Weiss D, Vega JD, Taylor WR, 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. 2007; 292:H1479–H1486.

33. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med. 2013; 368:2004–2013.

34. Nakamura K, Sasaki T, Cheng XW, Iguchi A, Sato K, Kuzuya M. Statin prevents plaque disruption in apoE-knockout mouse model through pleiotropic effect on acute inflammation. Atherosclerosis. 2009; 206:355–361.

35. Hermus L, Lefrandt JD, Tio RA, Breek JC, Zeebregts CJ. Carotid plaque formation and serum biomarkers. Atherosclerosis. 2010; 213:21–29.

36. Geluk CA, Post WJ, Hillege HL, Tio RA, Tijssen JG, van Dijk RB, et al. C-reactive protein and angiographic characteristics of stable and unstable coronary artery disease: data from the prospective PREVEND cohort. Atherosclerosis. 2008; 196:372–382.

37. Liang J, Liu E, Yu Y, Kitajima S, Koike T, Jin Y, et al. Macrophage metalloelastase accelerates the progression of atherosclerosis in transgenic rabbits. Circulation. 2006; 113:1993–2001.

38. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002; 105:1135–1143.

39. Sukhova GK, Zhang Y, Pan JH, Wada Y, Yamamoto T, Naito M, et al. Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003; 111:897–906.

40. Sasaki T, Kuzuya M, Nakamura K, Cheng XW, Hayashi T, Song H, et al. AT1 blockade attenuates atherosclerotic plaque destabilization accompanied by the suppression of cathepsin S activity in apoE-deficient mice. Atherosclerosis. 2010; 210:430–437.

41. Schwartz SM, Galis ZS, Rosenfeld ME, Falk E. Plaque rupture in humans and mice. Arterioscler Thromb Vasc Biol. 2007; 27:705–713.

42. Fukuda D, Shimada K, Tanaka A, Kusuyama T, Yamashita H, Ehara S, et al. Comparison of levels of serum matrix metalloproteinase-9 in patients with acute myocardial infarction versus unstable angina pectoris versus stable angina pectoris. Am J Cardiol. 2006; 97:175–180.

43. Oörni K, Sneck M, Brömme D, Pentikäinen MO, Lindstedt KA, Mäyränpää M, 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. 2004; 279:34776–34784.

44. Lindstedt L, Lee M, Oörni K, Brömme D, Kovanen PT. Cathepsins F and S block HDL3-induced cholesterol efflux from macrophage foam cells. Biochem Biophys Res Commun. 2003; 312:1019–1024.