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Clusterin: a protective mediator for ischemic cardiomyocytes?
P A J Krijnen1, S A G M Cillessen, R Manoe
1VU Univ. Medical Center, Dept. of Pathology, De Boelelaan 1117, 1007 MB Amsterdam, The Netherlands. paj.krijnen@vumc.nl
Insights
Clusterin protects heart cells from ischemic injury by upregulating independently of complement. This finding reveals a novel protective mechanism for cardiomyocytes during heart attacks.
Area of Science:
- Cardiovascular Research
- Cellular Biology
- Immunology
Background:
- Acute myocardial infarction involves complex cellular stress responses.
- The role of clusterin and complement activation in cardiac injury is not fully understood.
Purpose of the Study:
- To investigate the relationship between clusterin and complement in human myocardial infarction.
- To evaluate clusterin's protective effects on cardiomyocytes under ischemic conditions.
Main Methods:
- Immunohistochemical analysis of clusterin and complement factor C3d in human infarcted hearts.
- In vitro studies using H9c2 cardiomyoblasts and isolated adult rat cardiomyocytes subjected to ischemia.
- Flow cytometry to analyze clusterin binding to cells.
- Cell viability assays to assess clusterin's protective effects.
Main Results:
- Clusterin was found on viable cardiomyocytes in human infarcts, distinct from complement deposition.
- Ischemia induced rapid clusterin expression in H9c2 cells, decreasing upon reperfusion.
- Clusterin bound to stressed and dying H9c2 cells.
- Clusterin significantly inhibited ischemia-induced cell death in both cell types, independent of complement.
Conclusions:
- Ischemia upregulates clusterin in viable cardiomyocytes.
- Clusterin confers protection against ischemic cell death through a complement-independent pathway.
- Clusterin represents a potential therapeutic target for mitigating myocardial infarction damage.
Abstract:
We examined the relationship between clusterin and activated complement in human heart infarction and evaluated the effect of this protein on ischemic rat neonatal cardiomyoblasts (H9c2) and isolated adult ventricular rat cardiomyocytes as in vitro models of acute myocardial infarction. Clusterin protects cells by inhibiting complement and colocalizes with complement on jeopardized human cardiomyocytes after infarction. The distribution of clusterin and complement factor C3d was evaluated in the infarcted human heart. We also analyzed the protein expression of clusterin in ischemic H9c2 cells. The binding of endogenous and purified human clusterin on H9c2 cells was analyzed by flow cytometry. Furthermore, the effect of clusterin on the viability of ischemically challenged H9c2 cells and isolated adult ventricular rat cardiomyocytes was analyzed. In human myocardial infarcts, clusterin was found on scattered, morphologically viable cardiomyocytes within the infarcted area that were negative for complement. In H9c2 cells, clusterin was rapidly expressed after ischemia. Its expression was reduced after reperfusion. Clusterin bound to single annexin V-positive or annexin V and propidium iodide-positive H9c2 cells. Clusterin inhibited ischemia-induced death in H9c2 cells as well as in isolated adult ventricular rat cardiomyocytes in the absence of complement. We conclude that ischemia induces the upregulation of clusterin in ischemically challenged, but viable, cardiomyocytes. Our data suggest that clusterin protects cardiomyocytes against ischemic cell death via a complement-independent pathway.
