0375: Re-evaluation of the role of mast cell in cardiac tissue following myocardial infarction

Abstract

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 ( Cpa3 Cre/+ mice). The number of mast cell progenitor (Lin - CD45 + CD34 + FcγRII/III + β7 + ) increased in the bone marrow and the white adipose tissue on day 3 after MI, infiltrated the heart on day 5 and differentiated to mature mast cells (Cd117 + FcεRI + Sca1 + ) by day 7 in cardiac tissue. To assess the functional effect of mast cell infiltration, the cardiac function 14 days following MI was assessed in wild-type (WT) and 3 mast cells deficient mice models, the kit W/Wv mice, the Cpa3 Cre/+ mice and mice treated with the degranulation inhibitor DSCG (50 μg/g, once a day). There was a significant decrease of the left ventricular shortening fraction in all 3 mast cell deficient models compared to WT mice (1.4-, 1.6- and 2-fold respectively) that correlated with increased cardiomyocyte apoptosis in the kit W/Wv mice; and increased fibrosis in the DSCG-treated mice (n=8-14 per group, p <0.01 vs WT). Interestingly, in the Cpa3 Cre/+ mice there were no differences on post-MI cardiac remodeling, but instead we observed a significant reduction in cardiomyocyte contractility (both cell shortening and maximal contracting velocity) with no effect on Ca 2+ transient peak or sarcoplasmic reticulum load. 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, Ca 2+ cycling independently. Identification of the molecular regulators involved in the cardiac effect of mast cell will provide a new platform of regulators with potential therapeutic properties.