Increased aldehyde-modification of collagen type IV in symptomatic plaques – A possible cause of endothelial dysfunction

Abstract

Increased aldehyde-modification of collagen type IV in symptomatic plaques -A possible cause of endothelial dysfunction.Dunér, Pontus; Goncalves, Isabel; Grufman, Helena; Edsfeldt, Andreas; To, Fong; Nitulescu, Mihaela; Nilsson, Jan; Bengtsson, Eva Link to publication Citation for published version (APA): Dunér, P., Goncalves, I., Grufman, H., Edsfeldt, A., To, F., Nitulescu, M., ... Bengtsson, E. (2015). Increased aldehyde-modification of collagen type IV in symptomatic plaques -A possible cause of endothelial dysfunction. Atherosclerosis, 240(1), 26-32. DOI: 10.101626-32. DOI: 10. /j.atherosclerosis.2015 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Abstract ObjectiveSubendothelial 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 apolipoproteinB100. 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. MethodsThe 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. ResultsPlaque 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. Autoantibodies 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. Conclusion 3The present observations imply that aldehyde-modification of collagen type IV, associated with LDL oxidation, in atherosclerotic plaques may cause endothelial d...

Autoantibodies against aldehyde‐modified collagen type IV are associated with risk of development of myocardial infarction

“…We have recently shown that MDA-modified collagen (MDA-collagen) type IV is present in lipid-rich regions of human plaques, supporting the notion that LDL oxidation induces MDA modification of ECM proteins [32]. Of interest, the level of autoantibodies against MDA-collagen type IV in plasma correlated with the amount of MDA-collagen type IV in the lesions [32]. Of interest, the level of autoantibodies against MDA-collagen type IV in plasma correlated with the amount of MDA-collagen type IV in the lesions [32].…”

“…In individuals with diabetes, glycosylation of collagen type IV interferes with the disposition and integrity of the protein which could affect the normal function of basement membranes [33]. We have recently shown that MDA-modified collagen (MDA-collagen) type IV is present in lipid-rich regions of human plaques, supporting the notion that LDL oxidation induces MDA modification of ECM proteins [32]. Furthermore, MDA-collagen type IV was increased in carotid plaques from symptomatic patients compared to plaques from asymptomatic patients.…”

“…IgM and IgG autoantibodies against MDA-collagen type IV were measured using an enzyme-linked immunosorbent assay (ELISA) [32]. First, 96-well microtitre plates were coated with 10 lg mL À1 collagen type IV and MDA-collagen type IV in PBS and incubated at 4°C overnight.…”

“…Collagen type IV is also known to be involved in smooth muscle cell (SMC) migration and is important for maintaining SMC quiescence [30]. MDA modification of collagen type IV reduces adhesion and anticoagulant properties of endothelial cells [31,32]. In individuals with diabetes, glycosylation of collagen type IV interferes with the disposition and integrity of the protein which could affect the normal function of basement membranes [33].…”

Prediction of acute coronary syndromes by urinary proteome analysis

“…They may also include altered covalent cross linking of collagens by lysyl oxidases (LOX) and/or oxidative modification e.g. by reactive aldehydes originating from oxidized low-density-lipoprotein [41] within the ECM. Collagens influence the function and activity of cells in the arterial wall, i.e.…”