Intravenous clusterin administration reduces myocardial infarct size in rats

Annemieke Van Dijk, Rob A. Vermond, Paul A J Krijnen, Lynda J M Juffermans, Nynke E. Hahn, Sudesh P Makker, Lucien A. Aarden, Erik Hack, Marieke Spreeuwenberg, Bert C. Van Rossum, Cristof Meischl, Walter J. Paulus, Florine J. Van Milligen, Hans W M Niessen

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Abstract

Background Clusterin (Apolipoprotein J), a plasma protein with cytoprotective and complement-inhibiting activities, localizes in the infarcted heart during myocardial infarction (MI). Recently, we have shown a protective effect of exogenous clusterin in vitro on ischaemically challenged cardiomyocytes independent of complement. We therefore hypothesized that intravenous clusterin administration would reduce myocardial infarction damage. Methods Wistar rats undergoing experimental MI, induced by 40 min ligation of a coronary vessel, were treated with either clusterin (n = 15) or vehicle (n = 13) intravenously, for 3 days post-MI. After 4 weeks, hearts were analysed. The putative role of megalin, a clusterin receptor, was also studied. Results Administration of human clusterin significantly reduced both infarct size (with 75 ± 5%) and death of animals (23% vehicle group vs. 0% clusterin group). Importantly, histochemical analysis showed no signs of impaired wound healing in the clusterin group. In addition, significantly increased numbers of macrophages were found in the clusterin group. We also found that the clusterin receptor megalin was present on cardiomyocytes in vitro which, however, was not influenced by ischaemia. Human clusterin co-localized with this receptor in vitro, but not in the human heart. In addition, using a megalin inhibitor, we found that clusterin did not exert its protective effect on cardiomyocytes through megalin. Conclusions Our results thus show that clusterin has a protective effect on cardiomyocytes after acute myocardial infarction in vivo, independent of its receptor megalin. This indicates that clusterin, or a clusterin derivate, is a potential therapeutic agent in the treatment of MI.

Original languageEnglish (US)
Pages (from-to)893-902
Number of pages10
JournalEuropean Journal of Clinical Investigation
Volume40
Issue number10
DOIs
StatePublished - Oct 2010

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Clusterin
Intravenous Administration
Rats
Myocardial Infarction
Low Density Lipoprotein Receptor-Related Protein-2
Cardiac Myocytes
Macrophages

Keywords

  • Clusterin
  • inflammation
  • myocardial infarction

ASJC Scopus subject areas

  • Medicine(all)
  • Clinical Biochemistry
  • Biochemistry

Cite this

Van Dijk, A., Vermond, R. A., Krijnen, P. A. J., Juffermans, L. J. M., Hahn, N. E., Makker, S. P., ... Niessen, H. W. M. (2010). Intravenous clusterin administration reduces myocardial infarct size in rats. European Journal of Clinical Investigation, 40(10), 893-902. https://doi.org/10.1111/j.1365-2362.2010.02345.x

Intravenous clusterin administration reduces myocardial infarct size in rats. / Van Dijk, Annemieke; Vermond, Rob A.; Krijnen, Paul A J; Juffermans, Lynda J M; Hahn, Nynke E.; Makker, Sudesh P; Aarden, Lucien A.; Hack, Erik; Spreeuwenberg, Marieke; Van Rossum, Bert C.; Meischl, Cristof; Paulus, Walter J.; Van Milligen, Florine J.; Niessen, Hans W M.

In: European Journal of Clinical Investigation, Vol. 40, No. 10, 10.2010, p. 893-902.

Research output: Contribution to journalArticle

Van Dijk, A, Vermond, RA, Krijnen, PAJ, Juffermans, LJM, Hahn, NE, Makker, SP, Aarden, LA, Hack, E, Spreeuwenberg, M, Van Rossum, BC, Meischl, C, Paulus, WJ, Van Milligen, FJ & Niessen, HWM 2010, 'Intravenous clusterin administration reduces myocardial infarct size in rats', European Journal of Clinical Investigation, vol. 40, no. 10, pp. 893-902. https://doi.org/10.1111/j.1365-2362.2010.02345.x
Van Dijk, Annemieke ; Vermond, Rob A. ; Krijnen, Paul A J ; Juffermans, Lynda J M ; Hahn, Nynke E. ; Makker, Sudesh P ; Aarden, Lucien A. ; Hack, Erik ; Spreeuwenberg, Marieke ; Van Rossum, Bert C. ; Meischl, Cristof ; Paulus, Walter J. ; Van Milligen, Florine J. ; Niessen, Hans W M. / Intravenous clusterin administration reduces myocardial infarct size in rats. In: European Journal of Clinical Investigation. 2010 ; Vol. 40, No. 10. pp. 893-902.
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abstract = "Background Clusterin (Apolipoprotein J), a plasma protein with cytoprotective and complement-inhibiting activities, localizes in the infarcted heart during myocardial infarction (MI). Recently, we have shown a protective effect of exogenous clusterin in vitro on ischaemically challenged cardiomyocytes independent of complement. We therefore hypothesized that intravenous clusterin administration would reduce myocardial infarction damage. Methods Wistar rats undergoing experimental MI, induced by 40 min ligation of a coronary vessel, were treated with either clusterin (n = 15) or vehicle (n = 13) intravenously, for 3 days post-MI. After 4 weeks, hearts were analysed. The putative role of megalin, a clusterin receptor, was also studied. Results Administration of human clusterin significantly reduced both infarct size (with 75 ± 5{\%}) and death of animals (23{\%} vehicle group vs. 0{\%} clusterin group). Importantly, histochemical analysis showed no signs of impaired wound healing in the clusterin group. In addition, significantly increased numbers of macrophages were found in the clusterin group. We also found that the clusterin receptor megalin was present on cardiomyocytes in vitro which, however, was not influenced by ischaemia. Human clusterin co-localized with this receptor in vitro, but not in the human heart. In addition, using a megalin inhibitor, we found that clusterin did not exert its protective effect on cardiomyocytes through megalin. Conclusions Our results thus show that clusterin has a protective effect on cardiomyocytes after acute myocardial infarction in vivo, independent of its receptor megalin. This indicates that clusterin, or a clusterin derivate, is a potential therapeutic agent in the treatment of MI.",
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AU - Van Dijk, Annemieke

AU - Vermond, Rob A.

AU - Krijnen, Paul A J

AU - Juffermans, Lynda J M

AU - Hahn, Nynke E.

AU - Makker, Sudesh P

AU - Aarden, Lucien A.

AU - Hack, Erik

AU - Spreeuwenberg, Marieke

AU - Van Rossum, Bert C.

AU - Meischl, Cristof

AU - Paulus, Walter J.

AU - Van Milligen, Florine J.

AU - Niessen, Hans W M

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N2 - Background Clusterin (Apolipoprotein J), a plasma protein with cytoprotective and complement-inhibiting activities, localizes in the infarcted heart during myocardial infarction (MI). Recently, we have shown a protective effect of exogenous clusterin in vitro on ischaemically challenged cardiomyocytes independent of complement. We therefore hypothesized that intravenous clusterin administration would reduce myocardial infarction damage. Methods Wistar rats undergoing experimental MI, induced by 40 min ligation of a coronary vessel, were treated with either clusterin (n = 15) or vehicle (n = 13) intravenously, for 3 days post-MI. After 4 weeks, hearts were analysed. The putative role of megalin, a clusterin receptor, was also studied. Results Administration of human clusterin significantly reduced both infarct size (with 75 ± 5%) and death of animals (23% vehicle group vs. 0% clusterin group). Importantly, histochemical analysis showed no signs of impaired wound healing in the clusterin group. In addition, significantly increased numbers of macrophages were found in the clusterin group. We also found that the clusterin receptor megalin was present on cardiomyocytes in vitro which, however, was not influenced by ischaemia. Human clusterin co-localized with this receptor in vitro, but not in the human heart. In addition, using a megalin inhibitor, we found that clusterin did not exert its protective effect on cardiomyocytes through megalin. Conclusions Our results thus show that clusterin has a protective effect on cardiomyocytes after acute myocardial infarction in vivo, independent of its receptor megalin. This indicates that clusterin, or a clusterin derivate, is a potential therapeutic agent in the treatment of MI.

AB - Background Clusterin (Apolipoprotein J), a plasma protein with cytoprotective and complement-inhibiting activities, localizes in the infarcted heart during myocardial infarction (MI). Recently, we have shown a protective effect of exogenous clusterin in vitro on ischaemically challenged cardiomyocytes independent of complement. We therefore hypothesized that intravenous clusterin administration would reduce myocardial infarction damage. Methods Wistar rats undergoing experimental MI, induced by 40 min ligation of a coronary vessel, were treated with either clusterin (n = 15) or vehicle (n = 13) intravenously, for 3 days post-MI. After 4 weeks, hearts were analysed. The putative role of megalin, a clusterin receptor, was also studied. Results Administration of human clusterin significantly reduced both infarct size (with 75 ± 5%) and death of animals (23% vehicle group vs. 0% clusterin group). Importantly, histochemical analysis showed no signs of impaired wound healing in the clusterin group. In addition, significantly increased numbers of macrophages were found in the clusterin group. We also found that the clusterin receptor megalin was present on cardiomyocytes in vitro which, however, was not influenced by ischaemia. Human clusterin co-localized with this receptor in vitro, but not in the human heart. In addition, using a megalin inhibitor, we found that clusterin did not exert its protective effect on cardiomyocytes through megalin. Conclusions Our results thus show that clusterin has a protective effect on cardiomyocytes after acute myocardial infarction in vivo, independent of its receptor megalin. This indicates that clusterin, or a clusterin derivate, is a potential therapeutic agent in the treatment of MI.

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