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Cardioprotective effects of the extracellular chaperone clusterin in acute myocardial infarction
Louwana Allawa1, Antoine Poirier1,2, Pascale Pignon3
1CNRS, Inserm, Laboratoire MITOVASC, SFR ICAT, Univ Angers, Angers, France.
Insights
Clusterin (CLU) protects the heart during acute myocardial infarction (AMI) by neutralizing harmful extracellular histones. This reduces inflammation and infarct size, offering a novel therapeutic target for heart attack patients.
Area of Science:
- Cardiovascular Research
- Molecular Medicine
- Immunology
Background:
- Acute myocardial infarction (AMI) is a major global cause of death.
- Clusterin (CLU), an extracellular chaperone, shows potential cardioprotective effects.
- The precise mechanisms of CLU's cardioprotection, particularly its interaction with damage-associated molecular patterns (DAMPs), are not fully understood.
Purpose of the Study:
- To investigate the hypothesis that CLU protects against AMI by neutralizing extracellular histones.
- To elucidate the role of CLU in mitigating the inflammatory response post-AMI.
Main Methods:
- In vitro experiments assessed CLU's effect on histone-induced cell death under hypoxic conditions.
- In vivo studies utilized CLU-deficient and wild-type mice subjected to AMI to measure infarct size and inflammatory markers.
- Analysis included protein levels, cytokine expression (IL-6, IL-1β), NF-kB activation, and NLRP3 inflammasome activity.
- Circulating CLU-histone complexes were measured in patients with ST-segment elevation myocardial infarction (STEMI).
Main Results:
- Exogenous CLU significantly reduced histone-induced cell death in vitro.
- CLU levels were elevated in the ischemic zone post-AMI in mice.
- CLU-deficient mice exhibited larger infarct sizes compared to wild-type mice.
- CLU administration attenuated the post-AMI inflammatory response by decreasing IL-6, IL-1β, p-NF-kB p65, and NLRP3 inflammasome activation.
- Elevated circulating CLU-histone complexes were observed in STEMI patients versus healthy controls.
Conclusions:
- Clusterin (CLU) demonstrates significant cardioprotection in the context of acute myocardial infarction (AMI).
- This protective effect is mediated, at least in part, by CLU's ability to neutralize cytotoxic extracellular histones released from damaged heart tissue.
- CLU mitigates the inflammatory cascade following AMI, suggesting its therapeutic potential.
Background:
Acute myocardial infarction (AMI) remains one of the leading causes of mortality worldwide. Recently, a cardioprotective effect of clusterin (CLU), a ubiquitous extracellular chaperone, has been reported. However, the underlying mechanisms remain unresolved. We hypothesized that CLU exerts its protective effect on AMI by neutralizing cytotoxic and proinflammatory properties of extracellular histones, a new class of damage-associated molecular patterns (DAMPs), that are released after massive cell injury.
Methods And Results:
In vitro, we showed that exogenous CLU reduces histone-induced cell death in H9C2 cells after hypoxia-reoxygenation (.78 ± .15 vs. 1.39 ± .20; p = .0059). Moreover, we found increased CLU protein levels in the ischemic zone vs. non-ischemic zone after AMI in mice (p < .05). Correspondingly, CLU-deficient (CLU-/-) mice presented significantly increased infarct size vs. wild-type (CLU+/+) mice (46.29 ± 5.13% vs. 27.47 ± 1.92%; p = .0176). This cardioprotective effect of CLU is accompanied by an attenuation of the post-AMI proinflammatory response through a decrease in the expression of proinflammatory cytokines interleukin (IL)-6 and IL-1β, a decrease in phosphorylated nuclear factor kappa B (NF-kB) p65, as well as a decrease in the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Also, we found that in patients with acute ST-segment elevation myocardial infarction (STEMI), circulating CLU-histone complexes were significantly increased compared to healthy controls (p < .001).
Conclusions:
From these results, CLU protects the heart from inflammatory injury in AMI and this cardioprotection is due at least in part to its ability to neutralise extracellular histones released from the damaged tissue.
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