Potential protective role of apoprotein J (clusterin) in atherogenesis: binding to enzymatically modified low-density lipoprotein reduces fatty acid-mediated cytotoxicity.
Following entrapment in the arterial intima, low-density lipoprotein (LDL) can be modified by hydrolytic enzymes to yield a lipoprotein derivative that binds C-reactive protein, activates complement, and is rapidly taken up by monocytes/macrophages. Free fatty acids contained in enzymatically modified LDL (E-LDL) render the lipoprotein cytotoxic due to their capacity to trigger programmed cell death. Apoprotein J (ApoJ) alias clusterin is a multifunctional glycoprotein with cytoprotective and anti-inflammatory properties. It interacts with diverse substrates, is present in the intima and the media of arteries with atherosclerotic lesions and is also synthesized by smooth muscle cells during development of atherosclerosis. We report that ApoJ binds to E-LDL but not to native LDL. Binding resulted in marked reduction of cytotoxicity of E-LDL on smooth muscle cells, as revealed by determination of caspase activity, annexin binding, and cellular ATP. ApoJ was detected immunohistochemically in early atherosclerotic lesions, where it was found to co-localize with E-LDL. In atherosclerotic lesions, ApoJ may thus subserve protective functions through its capacity to inactivate C5b-9 complement complexes and by reducing the cytotoxic effects of modified LDL on cells that gain contact with the lipoprotein.
Schwarz
Margarethe
M
Institute of Medical Microbiology and Hygiene, Hochhaus am Augustusplatz, Obere Zahlbacher Strasse 67, 55101 Mainz, Germany.
Spath
Lena
L
Lux
Cornelia A
CA
Paprotka
Kerstin
K
Torzewski
Michael
M
Dersch
Katrin
K
Koch-Brandt
Claudia
C
Husmann
Matthias
M
Bhakdi
Sucharit
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017302:Annexins / Q000378:metabolism; D017209:Apoptosis; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D051152:Clusterin / Q000097:blood / Q000378:metabolism*; D003167:Complement Activation; D019610:Cytoprotection; D004285:Dogs; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D006868:Hydrolysis; D007150:Immunohistochemistry; D008066:Lipolysis; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000633:toxicity; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011486:Protein C / Q000378:metabolism; D051381:Rats; D013997:Time Factors
D017302:Annexins; C495242:CLU protein, human; D051152:Clusterin; D005227:Fatty Acids; D008077:Lipoproteins, LDL; D011486:Protein C; D000255:Adenosine Triphosphate; D020169:Caspases