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American Heart Association

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Final ID: We073

CLEC4E Signaling in Myocardial Ischemia-Reperfusion Injury

Abstract Body: Background: The innate immune receptor CLEC4E (C-type lectin domain family 4 member E) in cardiac resident cells and circulating leukocytes contributes to ischemic myocardial damage and adverse LV remodeling following ischemia reperfusion injury (I/R). Mice with loss of CLEC4E gene function show reduced cardiac injury and better LV remodeling but the mechanisms of this cardioprotection remain unknown.

Aims: We investigated whether Clec4e gene function in cardiac resident cells vs infiltrating immune cells mediates cardioprotection during myocardial ischemia-reperfusion injury.

Methods:We generated chimeric mice by IV infusion of 5 x 106 bone marrow cells originating from C57Bl6/J CLEC4E-/- and C57Bl6/J wild-type (WT) donor mice in 8w-old lethally irradiated (9.5 Gy) WT (n=36) and CLEC4E-/- (n=50) receptor mice, respectively. After 4 w, mice were subjected to ischemia reperfusion injury (I/R) by 60 min LAD occlusion. Troponin levels (TnI) were measured at 90 min post I/R and 7T-magnetic resonance imaging with late gadolinium enhancement (LGE) for infarct size evaluation was performed at 24 h and 28 d post I/R. Mice were euthanized at 28 days for immunohistochemistry and analysis of BM chimerism.

Results:Immunohistochemistry for CLEC4E expression on bone marrow smears confirmed successful BM chimerism. At 24h post I/R, TnI levels and LGE-assessed infarct size on MRI were not significantly different between groups (42.1 vs 48.4 ng/ml, and 25.2% vs 31.5% of LVmass in CLEC4E-/- & WT BM versus in WT & CLEC4E-/- BM, respectively) suggesting similar myocardial damage . After 28 d, LV end-diastolic volumes (43µL vs 55µL), and end-systolic volumes (13µL vs 25µL) were significantly smaller in CLEC4E-/- & WT BM than in WT & CLEC4E-/- BM mice (P<0.05 for both), resulting in better preserved global LV function (LVEF 62% vs 47%, P<0.05) . Infarct size, semiquantitatively assessed using planimetry on Sirius red stains, was smaller in CLEC4E-/- & WT BM than in WT & CLEC4E-/- BM (6.9% vs 19.8%, P<0.01).
Conclusion: CLEC4E gene deletion in cardiac resident cells, but not in infiltrating hematopoietic immune cells is associated with better functional and structural remodelling after myocardial I/R. Inhibition of CLEC4E signaling via blocking antibodies or small molecule inhibitors in cardiac myocytes might be a promising cardioprotective strategy.
  • Algoet, Michiel  ( KU Leuven , Leuven , Belgium )
  • Pusovnik, Matic  ( K.U. Leuven , Leuven , Belgium )
  • Caluwe, Ellen  ( KU Leuven , Leuven , Belgium )
  • Gillijns, Hilde  ( KU Leuven , Leuven , Belgium )
  • Gsell, Willy  ( K.U. Leuven , Leuven , Belgium )
  • Himmelreich, Uwe  ( K.U. Leuven , Leuven , Belgium )
  • Oosterlinck, Wouter  ( KU Leuven , Leuven , Belgium )
  • Janssens, Stefan  ( KU Leuven , Leuven , Belgium )
  • Author Disclosures:
    Michiel Algoet: DO NOT have relevant financial relationships | Matic Pusovnik: DO NOT have relevant financial relationships | Ellen Caluwe: DO NOT have relevant financial relationships | Hilde Gillijns: DO NOT have relevant financial relationships | Willy Gsell: DO NOT have relevant financial relationships | Uwe Himmelreich: No Answer | Wouter Oosterlinck: No Answer | Stefan Janssens: DO NOT have relevant financial relationships
Meeting Info:

Basic Cardiovascular Sciences

2024

Chicago, Illinois

Session Info:

Poster Session and Reception 3

Wednesday, 07/24/2024 , 04:30PM - 07:00PM

Poster Session and Reception

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