Genetic Deficiency and Pharmacological Stabilization of Mast Cells Ameliorate Pressure Overload-Induced Maladaptive Right Ventricular Remodeling in Mice

Abstract

Although the response of the right ventricle (RV) to the increased afterload is an important determinant of the patient outcome, very little is known about the underlying mechanisms. Mast cells have been implicated in the pathogenesis of left ventricular maladaptive remodeling and failure. However, the role of mast cells in RV remodeling remains unexplored. We subjected mast cell-deficient WBB6F1-KitW/W-v (KitW/KitW-v) mice and their mast cell-sufficient littermate controls (MC+/+) to pulmonary artery banding (PAB). PAB led to RV dilatation, extensive myocardial fibrosis, and RV dysfunction in MC+/+ mice. In PAB KitW/KitW-v mice, RV remodeling was characterized by minimal RV chamber dilatation and preserved RV function. We further administered to C57Bl/6J mice either placebo or cromolyn treatment starting from day 1 or 7 days after PAB surgery to test whether mast cells stabilizing drugs can prevent or reverse maladaptive RV remodeling. Both preventive and therapeutic cromolyn applications significantly attenuated RV dilatation and improved RV function. Our study establishes a previously undescribed role of mast cells in pressure overload-induced adverse RV remodeling. Mast cells may thus represent an interesting target for the development of a new therapeutic approach directed specifically at the heart.

Right‐ventricular dysfunction in HFpEF is linked to altered cardiomyocyte Ca2+ homeostasis and myofilament sensitivity

“…48 For cardiac MRI recordings, similarly, the obesity of ZSF-1 obese animals made them incompatible with the bore of the machine available to us (MRsolutions MRS3017), a system already fitted to be compatible with overweight small animals. On this account, M-mode imaging of the RV in the parasternal long-axis view is the preferred method in studies featuring small animal echocardiography [49][50][51] and-given its high temporal and spatial resolution-viewed as the accepted approach to assess relative RV dimensions and function.…”

Mast Cells in Cardiac Remodeling: Focus on the Right Ventricle

“…Treatment of wild-type mice subjected to pressure overload by PAB with the mast cell stabilizer cromolyn significantly improved RV remodeling and function [87]. Similarly, mast cell-deficient Kit W /Kit W-v mice subjected to PAB showed minimal RV dilation and preserved RV function [87]. These beneficial changes in RV remodeling were associated with reduced gene expressions in the RV of proinflammatory cytokines, such as TNF-α and IL-6 [87].…”

“…Observations in PAB rats showed that mast cell density in the RV was significantly increased as late as 200 days following pressure overload induction [119]. The evidence for the pathological role of mast cells in adverse RV remodeling was further provided in experiments exploiting mast cell-deficient mice and pharmacological inhibition of mast cell activation [87]. Treatment of wild-type mice subjected to pressure overload by PAB with the mast cell stabilizer cromolyn significantly improved RV remodeling and function [87].…”

“…The evidence for the pathological role of mast cells in adverse RV remodeling was further provided in experiments exploiting mast cell-deficient mice and pharmacological inhibition of mast cell activation [87]. Treatment of wild-type mice subjected to pressure overload by PAB with the mast cell stabilizer cromolyn significantly improved RV remodeling and function [87]. Similarly, mast cell-deficient Kit W /Kit W-v mice subjected to PAB showed minimal RV dilation and preserved RV function [87].…”

Novel Therapeutic Targets for the Treatment of Right Ventricular Remodeling: Insights from the Pulmonary Artery Banding Model

“…For example, an increased content of mast cells was observed in the RV upon pressure overload in PAB mice [83]. The mast cell stabilizer cromolyn prevented and reversed RV remodeling in PAB mice when applied from day 1 or day 7 after PAB operation, respectively [84]. Furthermore, both NF-κβ and TLR9 inhibitors could improve RV remodeling, fibrosis, and function by attenuating myocardial inflammation in PAB rats [85].…”