Mast cells in pressure overload induced right ventricular remodeling

Abstract

Numerous studies have recently implicated mast cells in cardiovascular diseases. However, the role of mast cells in the development of right ventricular (RV) hypertrophy is not known. RV hypertrophy was induced in C57Bl/6 and WBB6F1/J-KitW/KitW-v (MCdeficient) and their wild type littermate mice by pulmonary artery banding (PAB). Mast cell stabilization in C57Bl/6 mice with cromolyn sodium was performed starting either from day 0 of PAB (early intervention) for 3 weeks or day 7 (late intervention) for 2 weeks. The functional changes of RV were assessed by high resolution ultrasound echocardiography. Hemodynamics, RV hypertrophy, RV mast cell density, mast cell activation/degranulation, RV interstitial fibrosis, cardiomyocyte hypertrophy, capillary density, mRNA expression of hypertrophic, profibrotic and mast cell specific genes were evaluated. Pressure overload-induced RV remodeling in banded C57Bl/6 mice was characterized by significant interstitial fibrosis, increased mast cell activity and RV dysfunction. Inhibition of mast cell degranulation significantly reduced RV interstitial fibrosis and decreased mRNA expression of genes for collagen 1 and 3 and mast cell proteases 4 and 5. Moreover, these changes were associated with significantly improved RV function (cardiac output, myocardial performance index and tricuspid annular plane systolic excursion). Furthermore, we observed a beneficial RV remodeling characterized by the absence of interstitial fibrosis and chamber dilatation with preserved RV function in mast cell-deficient mice. These improvements were associated with decreased SMAD phosphorylation in mast cell-deficient mice. Our data suggest that mast cells play a critical role in the pressure overload-induced RV remodeling. Stabilization of mast cells may represent a new approach in the RV-directed therapy.