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

  • Pontus Dunér
    Correspondence
    Corresponding author. Department of Clinical Sciences, Jan Waldenströms Gata 35, 20502 Malmö, Sweden.
    Affiliations
    Experimental Cardiovascular Research Unit, Clinical Research Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
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  • Isabel Gonçalves
    Affiliations
    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
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  • Helena Grufman
    Affiliations
    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
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  • Andreas Edsfeldt
    Affiliations
    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
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  • Fong To
    Affiliations
    Experimental Cardiovascular Research Unit, Clinical Research Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
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  • Mihaela Nitulescu
    Affiliations
    Experimental Cardiovascular Research Unit, Clinical Research Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
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  • Jan Nilsson
    Affiliations
    Experimental Cardiovascular Research Unit, Clinical Research Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
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  • Eva Bengtsson
    Affiliations
    Experimental Cardiovascular Research Unit, Clinical Research Center, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
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      Highlights

      • Subendothelial LDL-adhesion is a key event in the atherosclerotic lesion formation.
      • During oxidation aldehydes could leak out of the LDL-particle and modify nearby matrix proteins.
      • Aldehyde-collagen type IV correlated with oxidized LDL and was increased in symptomatic lesions.
      • Aldehyde-modification of collagen type IV decreased endothelial cell attachment.
      • Aldehyde-modification of collagen type IV may cause endothelial dysfunction and increase the risk of clinical events.

      Abstract

      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.

      Conclusion

      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.

      Keywords

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