Intravenous clusterin administration reduces myocardial infarct size in rats.
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.
Van Dijk
Annemieke
A
Department of Pathology, VU Medical Center, Amsterdam, The Netherlands. Annemieke.vandijk@vumc.nl
Vermond
Rob A
RA
Krijnen
Paul A J
PA
Juffermans
Lynda J M
LJ
Hahn
Nynke E
NE
Makker
Sudesh P
SP
Aarden
Lucien A
LA
Hack
Erik
E
Spreeuwenberg
Marieke
M
van Rossum
Bert C
BC
Meischl
Cristof
C
Paulus
Walter J
WJ
Van Milligen
Florine J
FJ
Niessen
Hans W M
HW
D000818:Animals; D051152:Clusterin / Q000627:therapeutic use*; D007150:Immunohistochemistry; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
D051152:Clusterin; D026561:Low Density Lipoprotein Receptor-Related Protein-2