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

Akylbek Sydykov,Friedrich Grimminger,Himal Luitel,Argen Mamazhakypov,Kabita Pradhan,Aleksandar Petrovic,Ralph Theo Schermuly,Oleg Pak,Malgorzata Wygrecka,Norbert Weissmann,Hossein Ardeschir Ghofrani,Djuro Kosanovic,Baktybek Kojonazarov,Werner Seeger

doi:10.3390/ijms21239099

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.

Highlights

Right ventricular (RV) remodeling in response to chronic pressure overload represents a complex set of functional and structural adaptations
Invasive measurements showed a significant pulmonary artery banding (PAB)-induced increase in right ventricular systolic pressure (RVSP) in both mast cell deficient KitW/KitW-v and mast cell-sufficient littermate control (MC+/+) mice compared to sham mice (Figure 1A)
The severity of the pressure overload imposed on the right ventricle of KitW/KitW-v and MC+/+ mice was comparable as evidenced by similar values of RVSP (Figure 1A)

Summary

Introduction

Right ventricular (RV) remodeling in response to chronic pressure overload represents a complex set of functional and structural adaptations. Accumulating evidence indicates that some molecular mechanisms underlying responses to increased afterload differ between the right and left ventricles [3,4]. Identifying these cellular and molecular targets that are differentially altered in the pressure overloaded right ventricle might help developing novel therapeutic approaches directed at the right ventricle. Identifying the shared pathways may allow extrapolation of medical therapies used in left heart failure to the treatment of RV failure Targeting these common pathways may lead to novel strategies applicable to the treatment of both right and left heart failure

Objectives

Methods

Results