Published online before print May 15, 2003, doi: 10.1161/01.ATV.0000077207.49221.06
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2003 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Lysosomal Enzymes Are Released From Cultured Human Macrophages, Hydrolyze LDL In Vitro, and Are Present Extracellularly in Human Atherosclerotic Lesions
From the Wihuri Research Institute, Helsinki, Finland and Division of Human Genetics (H.D., G.A.G.), Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio.
Correspondence to Petri T. Kovanen, M.D., Ph.D., Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland. E-mail Petri.Kovanen{at}wri.fi
Objective— Human atherosclerotic lesions have been shown to contain lipid droplets and vesicles resembling those of in vitro enzymatically modified LDL. However, little is known about the hydrolytic enzymes in the arterial intima that induce fusion of LDL particles and so produce lipid droplets or that induce foam cell formation.
Methods and Results— Human coronary atherosclerotic lesions obtained at surgery and at autopsy were stained for lysosomal acid lipase and cathepsin D. The extracellular areas of macrophage-rich intimal regions of the atherosclerotic lesions stained positively for both cathepsin D and lysosomal acid lipase, whereas normal arteries were negative. When monocyte-derived macrophages were incubated with opsonized zymosan to stimulate the release of lysosomal enzymes from the cells and LDL was incubated with the macrophage-conditioned media, the apolipoprotein B-100, cholesteryl esters, and triacylglycerols of LDL were hydrolyzed. These hydrolytic modifications rendered the LDL particles unstable and induced their fusion. Cultured macrophages and smooth muscle cells took up the hydrolase-modified LDL particles avidly and were transformed into foam cells.
Conclusions— Our in vivo and in vitro results suggest that lysosomal enzymes released from macrophages may induce hydrolytic modification of LDL and foam cell formation in the human arterial intima.
Key Words: macrophage • lysosomal enzymes • LDL • atherosclerosis
This article has been cited by other articles:
 |
|
 |
|
  S. Erdmann, A. Ricken, C. Merkwitz, I. Struman, R. Castino, K. Hummitzsch, F. Gaunitz, C. Isidoro, J. Martial, and K. Spanel-Borowski The expression of prolactin and its cathepsin D-mediated cleavage in the bovine corpus luteum vary with the estrous cycle Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1365 - E1377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wen and D. S. Leake Low Density Lipoprotein Undergoes Oxidation Within Lysosomes in Cells Circ. Res., May 11, 2007; 100(9): 1337 - 1343. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. K SUKHOVA and G.-P. SHI Do Cathepsins Play a Role in Abdominal Aortic Aneurysm Pathogenesis? Ann. N.Y. Acad. Sci., November 1, 2006; 1085(1): 161 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Hakala, K. A. Lindstedt, P. T. Kovanen, and M. O. Pentikainen Low-Density Lipoprotein Modified by Macrophage-Derived Lysosomal Hydrolases Induces Expression and Secretion of IL-8 Via p38 MAPK and NF-{kappa}B by Human Monocyte-Derived Macrophages Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2504 - 2509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Rodgers, D. J. Watkins, A. L. Miller, P. Y. Chan, S. Karanam, W. H. Brissette, C. J. Long, and C. L. Jackson Destabilizing Role of Cathepsin S in Murine Atherosclerotic Plaques Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 851 - 856. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Lutgens, S.P.M. Lutgens, B.C.G. Faber, S. Heeneman, M.M.J. Gijbels, M.P.J. de Winther, P. Frederik, I. van der Made, A. Daugherty, A.M. Sijbers, et al. Disruption of the Cathepsin K Gene Reduces Atherosclerosis Progression and Induces Plaque Fibrosis but Accelerates Macrophage Foam Cell Formation Circulation, January 3, 2006; 113(1): 98 - 107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sneck, P. T. Kovanen, and K. Oorni Decrease in pH Strongly Enhances Binding of Native, Proteolyzed, Lipolyzed, and Oxidized Low Density Lipoprotein Particles to Human Aortic Proteoglycans J. Biol. Chem., November 11, 2005; 280(45): 37449 - 37454. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Fuster, P. R. Moreno, Z. A. Fayad, R. Corti, and J. J. Badimon Atherothrombosis and High-Risk Plaque: Part I: Evolving Concepts J. Am. Coll. Cardiol., September 20, 2005; 46(6): 937 - 954. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. LI and X.-M. YUAN Increased Expression and Translocation of Lysosomal Cathepsins Contribute to Macrophage Apoptosis in Atherogenesis Ann. N.Y. Acad. Sci., December 1, 2004; 1030(1): 427 - 433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Torzewski, P. Suriyaphol, K. Paprotka, L. Spath, V. Ochsenhirt, A. Schmitt, S.-R. Han, M. Husmann, V. B. Gerl, S. Bhakdi, et al. Enzymatic Modification of Low-Density Lipoprotein in the Arterial Wall: A New Role for Plasmin and Matrix Metalloproteinases in Atherogenesis Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): 2130 - 2136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Camejo Hydrolytic Enzymes Released From Resident Macrophages and Located in the Intima Extracellular Matrix as Agents That Modify Retained Apolipoprotein B Lipoproteins Arterioscler. Thromb. Vasc. Biol., August 1, 2003; 23(8): 1312 - 1313. [Full Text] [PDF]
|
|