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Updated: Apr 1, 2026
Ex Vivo Corneal Organ Culture Model for Wound Healing Studies
Published on: February 15, 2019
Calpastatin overexpression impairs postinfarct scar healing in mice by compromising reparative immune cell
Feng Wan1, Emmanuel Letavernier2, Claude Jourdan Le Saux3
1Institut National de la Santé et de la Recherche Médicale U955, Université Paris-Est Creteil, Créteil, France;
Abstract:
The activation of the calpain system is involved in the repair process following myocardial infarction (MI). However, the impact of the inhibition of calpain by calpastatin, its natural inhibitor, on scar healing and left ventricular (LV) remodeling is elusive. Male mice ubiquitously overexpressing calpastatin (TG) and wild-type (WT) controls were subjected to an anterior coronary artery ligation. Mortality at 6 wk was higher in TG mice (24% in WT vs. 44% in TG, P < 0.05) driven by a significantly higher incidence of cardiac rupture during the first week post-MI, despite comparable infarct size and LV dysfunction and dilatation. Calpain activation post-MI was blunted in TG myocardium. In TG mice, inflammatory cell infiltration and activation were reduced in the infarct zone (IZ), particularly affecting M2 macrophages and CD4(+) T cells, which are crucial for scar healing. To elucidate the role of calpastatin overexpression in macrophages, we stimulated peritoneal macrophages obtained from TG and WT mice in vitro with IL-4, yielding an abrogated M2 polarization in TG but not in WT cells. Lymphopenic Rag1(-/-) mice receiving TG splenocytes before MI demonstrated decreased T-cell recruitment and M2 macrophage activation in the IZ day 5 after MI compared with those receiving WT splenocytes. Calpastatin overexpression prevented the activation of the calpain system after MI. It also impaired scar healing, promoted LV rupture, and increased mortality. Defective scar formation was associated with blunted CD4(+) T-cell and M2-macrophage recruitment.
Insights
Inhibiting calpain with calpastatin after myocardial infarction (MI) impairs scar healing and increases cardiac rupture and mortality. This is linked to reduced T-cell and M2 macrophage recruitment to the injured heart tissue.
Area of Science:
- Cardiovascular Biology
- Immunology
- Regenerative Medicine
Background:
- Calpain system activation is crucial for myocardial infarction (MI) repair.
- The role of calpastatin, the natural calpain inhibitor, in cardiac scar healing and left ventricular (LV) remodeling post-MI remains unclear.
Purpose of the Study:
- To investigate the effects of calpastatin overexpression on cardiac repair and remodeling following MI.
- To determine the impact of calpastatin on inflammatory cell infiltration and macrophage polarization in the infarct zone.
Main Methods:
- Male mice overexpressing calpastatin (TG) and wild-type (WT) controls underwent coronary artery ligation to induce MI.
- Mortality, cardiac rupture, infarct size, and LV function were assessed.
- Inflammatory cell infiltration (M2 macrophages, CD4+ T cells) in the infarct zone was analyzed.
- In vitro studies assessed M2 polarization of macrophages from TG and WT mice.
- Adoptive transfer of splenocytes into lymphopenic mice evaluated T-cell and macrophage recruitment post-MI.
Main Results:
- TG mice exhibited higher mortality (44% vs. 24%) due to increased cardiac rupture within the first week post-MI.
- Calpain activation was blunted in TG mice, with reduced inflammatory cell infiltration, particularly M2 macrophages and CD4+ T cells.
- In vitro, TG macrophages showed abrogated M2 polarization upon IL-4 stimulation.
- Splenocyte transfer from TG mice led to decreased T-cell recruitment and M2 macrophage activation in the infarct zone.
Conclusions:
- Calpastatin overexpression impairs cardiac scar healing and promotes adverse LV remodeling post-MI.
- Reduced recruitment and activation of CD4+ T cells and M2 macrophages contribute to defective scar formation.
- Inhibition of the calpain system by calpastatin increases mortality following myocardial infarction.
