Increased aldehyde-modification of collagen type IV in symptomatic plaques--a possible cause of endothelial dysfunction.
OBJECTIVE
Subendothelial LDL-adhesion and its subsequent oxidation are considered as key events in the development of atherosclerotic lesions. During oxidation of LDL, reactive aldehydes such as malondialdehyde (MDA) are formed, which modify apolipoprotein B100. However, the possibility that these reactive aldehydes could leak out of the LDL-particle and modify surrounding extracellular matrix proteins has been largely unexplored. We have investigated if aldehyde-modification of collagen type IV, one of the major basement membrane components, in plaques is associated with cardiovascular events.


METHODS
The amount of MDA-modified collagen type IV and native collagen type IV were determined in homogenates from 155 carotid artery lesions, removed by endarterectomy from patients with or without previous cerebrovascular events.


RESULTS
Plaque MDA-collagen type IV, but not native collagen type IV, correlated with oxidized LDL (r=0.31, P<0.001) and lipoprotein-associated phospholipase A2 (r=0.44, P<0.001). MDA-collagen type IV was increased in lesions from symptomatic patients compared to lesions from asymptomatic patients. Auto-antibodies against MDA-collagen type IV in plasma correlated with the amount of MDA-collagen type IV in lesions. MDA-modification of collagen type IV decreased endothelial cell attachment. In addition, culture of endothelial cells with MDA-modified collagen type IV increased vascular cell adhesion molecule expression and reduced the anti-coagulant proteins thrombomodulin and endothelial protein C receptor. In the lesions native collagen type IV, but not MDA-collagen type IV, was positively associated with thrombomodulin.


CONCLUSIONS
The present observations imply that aldehyde-modification of collagen type IV, associated with LDL oxidation, in atherosclerotic plaques may cause endothelial dysfunction and increase the risk of clinical events.
Experimental Cardiovascular Research Unit, Clinical Research Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden. Electronic address: pontus.duner@med.lu.se.
Pontus
P
Dunér
Experimental Cardiovascular Research Unit, Clinical Research Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden; Department of Cardiology, Lund University, Skåne University Hospital, Malmö, Sweden.
Isabel
I
Gonçalves
Experimental Cardiovascular Research Unit, Clinical Research Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden; Department of Cardiology, Lund University, Skåne University Hospital, Malmö, Sweden.
Helena
H
Grufman
Experimental Cardiovascular Research Unit, Clinical Research Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden; Department of Cardiology, Lund University, Skåne University Hospital, Malmö, Sweden.
Andreas
A
Edsfeldt
Experimental Cardiovascular Research Unit, Clinical Research Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
Fong
F
To
Experimental Cardiovascular Research Unit, Clinical Research Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
Mihaela
M
Nitulescu
Experimental Cardiovascular Research Unit, Clinical Research Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
Jan
J
Nilsson
Experimental Cardiovascular Research Unit, Clinical Research Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
Eva
E
Bengtsson
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism; D058070:Asymptomatic Diseases; D001323:Autoantibodies / Q000378:metabolism; D002339:Carotid Arteries / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000150:complications / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D002448:Cell Adhesion; D002478:Cells, Cultured; D002561:Cerebrovascular Disorders / Q000209:etiology; D024141:Collagen Type IV / Q000276:immunology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008315:Malondialdehyde / Q000276:immunology / Q000378:metabolism*; D058226:Plaque, Atherosclerotic; D011499:Protein Processing, Post-Translational; D018180:Thrombomodulin / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D001323:Autoantibodies; D024141:Collagen Type IV; D008077:Lipoproteins, LDL; C546931:THBD protein, human; D018180:Thrombomodulin; D019010:Vascular Cell Adhesion Molecule-1; C099252:oxidized low density lipoprotein; D008315:Malondialdehyde; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C526684:PLA2G7 protein, human
Aldehyde-modification; Collagen type IV; Endothelial dysfunction; LDL oxidation