Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Aug 1, 1998; 102(3): 576–583.
PMCID: PMC508918

Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells.


Formation of the atherosclerotic intima must involve altered metabolism of the elastin-rich arterial extracellular matrix. Proteases potentially involved in these processes remain unclear. This study examined the expression of the potent elastases cathepsins S and K in human atheroma. Normal arteries contained little or no cathepsin K or S. In contrast, macrophages in atheroma contained abundant immunoreactive cathepsins K and S. Intimal smooth muscle cells (SMC), especially cells appearing to traverse the internal elastic laminae, also contained these enzymes. Extracts of atheromatous tissues had approximately twofold greater elastase-specific activity than extracts of uninvolved arteries, mostly due to cysteine proteases. Cultured human SMC displayed no immunoreactive cathepsins K and S and exhibited little or no elastolytic activity when incubated with insoluble elastin. SMC stimulated with the atheroma-associated cytokines IL-1beta or IFN-gamma secreted active cathepsin S and degraded substantial insoluble elastin (15-20 microg/10(6) cells/24 h). A selective inhibitor of cathepsin S blocked > 80% of this elastolytic activity. The presence of cathepsins K and S at sites of vascular matrix remodeling and the ability of SMC and macrophages to use these enzymes to degrade elastin supports a role for elastolytic cathepsins in vessel wall remodeling and identifies novel therapeutic targets in regulating plaque stability.

Full Text

The Full Text of this article is available as a PDF (596K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Davies MJ. Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995. Circulation. 1996 Oct 15;94(8):2013–2020. [PubMed]
  • van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994 Jan;89(1):36–44. [PubMed]
  • Henney AM, Wakeley PR, Davies MJ, Foster K, Hembry R, Murphy G, Humphries S. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8154–8158. [PMC free article] [PubMed]
  • Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994 Dec;94(6):2493–2503. [PMC free article] [PubMed]
  • Galis ZS, Sukhova GK, Libby P. Microscopic localization of active proteases by in situ zymography: detection of matrix metalloproteinase activity in vascular tissue. FASEB J. 1995 Jul;9(10):974–980. [PubMed]
  • Zhu L, Wigle D, Hinek A, Kobayashi J, Ye C, Zuker M, Dodo H, Keeley FW, Rabinovitch M. The endogenous vascular elastase that governs development and progression of monocrotaline-induced pulmonary hypertension in rats is a novel enzyme related to the serine proteinase adipsin. J Clin Invest. 1994 Sep;94(3):1163–1171. [PMC free article] [PubMed]
  • Leake DS, Hornebeck W, Bréchemier D, Robert L, Peters TJ. Properties and subcellular localization of elastase-like activities of arterial smooth muscle cells in culture. Biochim Biophys Acta. 1983 Nov 22;761(1):41–47. [PubMed]
  • Xin XQ, Gunesekera B, Mason RW. The specificity and elastinolytic activities of bovine cathepsins S and H. Arch Biochem Biophys. 1992 Dec;299(2):334–339. [PubMed]
  • Shi GP, Munger JS, Meara JP, Rich DH, Chapman HA. Molecular cloning and expression of human alveolar macrophage cathepsin S, an elastinolytic cysteine protease. J Biol Chem. 1992 Apr 15;267(11):7258–7262. [PubMed]
  • Reddy VY, Zhang QY, Weiss SJ. Pericellular mobilization of the tissue-destructive cysteine proteinases, cathepsins B, L, and S, by human monocyte-derived macrophages. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3849–3853. [PMC free article] [PubMed]
  • Bossard MJ, Tomaszek TA, Thompson SK, Amegadzie BY, Hanning CR, Jones C, Kurdyla JT, McNulty DE, Drake FH, Gowen M, et al. Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J Biol Chem. 1996 May 24;271(21):12517–12524. [PubMed]
  • Brömme D, Okamoto K, Wang BB, 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. 1996 Jan 26;271(4):2126–2132. [PubMed]
  • Kafienah W, Brömme D, Buttle DJ, Croucher LJ, Hollander AP. Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochem J. 1998 May 1;331(Pt 3):727–732. [PMC free article] [PubMed]
  • Petanceska S, Devi L. Sequence analysis, tissue distribution, and expression of rat cathepsin S. J Biol Chem. 1992 Dec 25;267(36):26038–26043. [PubMed]
  • Brömme D, Bonneau PR, Lachance P, Wiederanders B, Kirschke H, Peters C, Thomas DY, Storer AC, Vernet T. Functional expression of human cathepsin S in Saccharomyces cerevisiae. Purification and characterization of the recombinant enzyme. J Biol Chem. 1993 Mar 5;268(7):4832–4838. [PubMed]
  • Rankin SM, Knowles ME, Leake DS. Macrophages possess both neutral and acidic protease activities toward low density lipoproteins. Atherosclerosis. 1989 Sep;79(1):71–78. [PubMed]
  • Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996 Aug 30;273(5279):1236–1238. [PubMed]
  • Littlewood-Evans AJ, Bilbe G, Bowler WB, Farley D, Wlodarski B, Kokubo T, Inaoka T, Sloane J, Evans DB, Gallagher JA. The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res. 1997 Dec 1;57(23):5386–5390. [PubMed]
  • Shi GP, Webb AC, Foster KE, Knoll JH, Lemere CA, Munger JS, Chapman HA. Human cathepsin S: chromosomal localization, gene structure, and tissue distribution. J Biol Chem. 1994 Apr 15;269(15):11530–11536. [PubMed]
  • Shi GP, Chapman HA, Bhairi SM, DeLeeuw C, Reddy VY, Weiss SJ. Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2. FEBS Lett. 1995 Jan 3;357(2):129–134. [PubMed]
  • Munger JS, Shi GP, Mark EA, Chin DT, Gerard C, Chapman HA. A serine esterase released by human alveolar macrophages is closely related to liver microsomal carboxylesterases. J Biol Chem. 1991 Oct 5;266(28):18832–18838. [PubMed]
  • Banda MJ, Werb Z, McKerrow JH. Elastin degradation. Methods Enzymol. 1987;144:288–305. [PubMed]
  • Libby P, O'Brien KV. Culture of quiescent arterial smooth muscle cells in a defined serum-free medium. J Cell Physiol. 1983 May;115(2):217–223. [PubMed]
  • Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995 Aug 1;92(3):657–671. [PubMed]
  • Werb Z, Bainton DF, Jones PA. Degradation of connective tissue matrices by macrophages. III. Morphological and biochemical studies on extracellular, pericellular, and intracellular events in matrix proteolysis by macrophages in culture. J Exp Med. 1980 Dec 1;152(6):1537–1553. [PMC free article] [PubMed]
  • Libby P, Ordovas JM, Birinyi LK, Auger KR, Dinarello CA. Inducible interleukin-1 gene expression in human vascular smooth muscle cells. J Clin Invest. 1986 Dec;78(6):1432–1438. [PMC free article] [PubMed]
  • Clinton SK, Fleet JC, Loppnow H, Salomon RN, Clark BD, Cannon JG, Shaw AR, Dinarello CA, Libby P. Interleukin-1 gene expression in rabbit vascular tissue in vivo. Am J Pathol. 1991 Apr;138(4):1005–1014. [PMC free article] [PubMed]
  • Baici A, Lang A. Effect of interleukin-1 beta on the production of cathepsin B by rabbit articular chondrocytes. FEBS Lett. 1990 Dec 17;277(1-2):93–96. [PubMed]
  • Huet G, Flipo RM, Colin C, Janin A, Hemon B, Collyn-d'Hooghe M, Lafyatis R, Duquesnoy B, Degand P. Stimulation of the secretion of latent cysteine proteinase activity by tumor necrosis factor alpha and interleukin-1. Arthritis Rheum. 1993 Jun;36(6):772–780. [PubMed]
  • Riese RJ, Wolf PR, Brömme D, Natkin LR, Villadangos JA, Ploegh HL, Chapman HA. Essential role for cathepsin S in MHC class II-associated invariant chain processing and peptide loading. Immunity. 1996 Apr;4(4):357–366. [PubMed]
  • Drake FH, Dodds RA, James IE, Connor JR, Debouck C, Richardson S, Lee-Rykaczewski E, Coleman L, Rieman D, Barthlow R, et al. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J Biol Chem. 1996 May 24;271(21):12511–12516. [PubMed]
  • Yamamoto M, Aoyagi M, Azuma H, Yamamoto K. Changes in osteopontin mRNA expression during phenotypic transition of rabbit arterial smooth muscle cells. Histochem Cell Biol. 1997 Apr;107(4):279–287. [PubMed]
  • Turtzo LC, Lee MD, Lu M, Smith BL, Copeland NG, Gilbert DJ, Jenkins NA, Agre P. Cloning and chromosomal localization of mouse aquaporin 4: exclusion of a candidate mutant phenotype, ataxia. Genomics. 1997 Apr 15;41(2):267–270. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...