Abstract 12169: Mast Cells Regulate Cardiomyocyte Contractility and Myofilament Ca2+ Sensitization Following Myocardial Infarction
Inflammatory cells orchestrate post-ischemic cardiac remodeling after myocardial infarction (MI). Studies in Kit mutant mice suggest key roles for mast cells in post-ischemic tissue remodeling. However, Kit mutations affect multiple cell types of both immune and non-immune origin. The aim of this study was to address the impact of mast cells on cardiac function following MI, using selectively mast cell-deficient mice (Cpa3Cre/+ mice).
The number of mast cell progenitors (Lin-CD45+CD34+FcγRII/III+β7+) increased on day 3 post MI in the bone marrow and the white adipose tissue and on day 5 in the heart. Mature mast cells (Cd117+FcεRI+Sca1+) peaked at day 7 in the cardiac tissue accompanied with a peak of mMCP4 and tryptase beta2 mRNA expression. To assess the functional effect of mast cell infiltration, the cardiac function 14 days post MI was assessed in WT, kitW/Wv and Cpa3Cre/+ mice. There was a significant decrease of the left ventricular shortening fraction in both the Cpa3Cre/+ and the kitW/Wv mice compared to WT mice (p<0.01, n=8-10). Although the reduction of heart function in the kitW/Wv mice correlated with increased cardiomyocyte apoptosis, there was no effect on cardiac remodeling (fibrosis, cardiomyocyte apoptosis or infarct size) observed in the Cpa3Cre/+ originated hearts. By contrast, in the Cpa3Cre/+ mice we observed a significant reduction in cardiomyocyte contractility (at 1, 2 & 4 Hz, 4ms pulse, 10volts amplitude) compared to WT. Cell shortening and maximal contracting/relaxing velocity were significantly decreased (p<0.01) with no effect on Ca2+ transient peak or sarcoplasmic reticulum load. Myofilament force-calcium relationships were measured in post-MI skinned myocytes. Compared to WT, calcium sensitivity declined significantly in Cpa3Cre/+ -derived myocytes (p<0.01) with no effect on maximal calcium-activated force.
This work re-evaluates existing mast-cell deficient models on their effect on cardiac remodeling and identifies a novel function for mast cells on modulation of cardiomyocyte contractility and Ca2+ sensitization. Identification of the mast cell-dependent molecular regulators that target myofilament proteins will provide a new platform of regulators with potential cardioprotective properties.
Author Disclosures: A. Ngkelo: None. J. Kirk: None. A. Richart: None. J. Vilar: None. P. Marck: None. C. Heymes: None. H. Rodewald: None. D. Kass: None. J. Silvestre: None.
- © 2014 by American Heart Association, Inc.