Abstract 213: Myofilament Ca2+ Sensitization and Site-specific Phosphorylation of Contractile Proteins Following Myocardial Infarction: A Novel Role for Mast Cells

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 (Cpa3Cre/+ mice). In response to myocardial infarction, mast cells progenitors’ numbers (Lin-CD45+CD34+FcγRII/IIIhighβ7+) increased in the white adipose tissue (day 3) and in the heart (day 5) and mature mast cells (CD117+FcεRI+Sca1+) peaked at day 7 in the cardiac tissue. To assess the functional effect of this mast cell infiltration in the heart, cardiac function 14 days following MI was assessed in wild-type (WT) and Cpa3Cre/+ mice. There was a significant decrease of the left ventricular shortening fraction in Cpa3Cre/+ compared to WT mice (17.27±1.9 % vs 28.15±1.7, p<0.01) that was not due to adverse cardiac remodeling; with no significant difference on levels of fibrosis, cardiomyocyte apoptosis, infarct size or neovascularization. By contrast, we observed a significant reduction in cardiomyocyte contractility (both cell shortening and ±dL/dt) in Cpa3Cre/+ mice compared to WT mice 14 days post MI. In addition, Ca2+ sensitivity (EC50) declined in Cpa3Cre/+ -derived skinned myocytes (p<0.01 vs WT) and correlated with increased PKA-dependent phosphorylation of both cardiac troponin (cTn)I (Ser22/23) and myosin-binding protein-C (MyBPC) (Ser273) (p<0.05). This study identifies a novel function of mast cells on modulating cardiomyocyte contractility via alteration of PKA-regulated Ca2+ handling and myofilament protein phosphorylation. Identification of the mast cell-dependent signaling pathway that targets cardiac performance will provide a new platform of regulators with potential cardioprotective properties.