Calpastatin overexpression impairs postinfarct scar healing in mice by compromising reparative immune cell recruitment and activation

Feng Wan, Emmanuel Letavernier, Claude Jourdan Le Saux, Amal Houssaini, Shariq Abid, Gabor Czibik, Daigo Sawaki, Elisabeth Marcos, Jean Luc Dubois-Rande, Laurent Baud, Serge Adnot, Geneviève Derumeaux, Barnabas Gellen

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)H1883-H1893
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume309
Issue number11
DOIs
StatePublished - 2015

Keywords

  • Calpain
  • Calpastatin
  • Cardiac rupture
  • Inflammation
  • Lymphocytes
  • Macrophages
  • Myocardial infarction
  • Scar healing

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Wan, F., Letavernier, E., Le Saux, C. J., Houssaini, A., Abid, S., Czibik, G., Sawaki, D., Marcos, E., Dubois-Rande, J. L., Baud, L., Adnot, S., Derumeaux, G., & Gellen, B. (2015). Calpastatin overexpression impairs postinfarct scar healing in mice by compromising reparative immune cell recruitment and activation. American Journal of Physiology - Heart and Circulatory Physiology, 309(11), H1883-H1893. https://doi.org/10.1152/ajpheart.00594.2015