Role of mast cells in pressure overload induced right ventricular remodeling and failure

• Applicant: Professor Dr. Ralph Schermuly
• Subject Area: Pneumology, Thoracic Surgery ; Cardiology, Angiology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280298313

Several types of congenital heart defects, pulmonary vascular diseases and left heart disease with increased pulmonary venous pressure lead to an increase in right ventricular afterload and right heart hypertrophy. While many investigations focused on the mechanisms of left heart hypertrophy, only limited information is available about the remodeling process of the right ventricle (RV). Most importantly, the RV performance defines prognosis in patients with congenital heart disease, pulmonary arterial hypertension, advanced left heart failure, and even in patients with stable cardiovascular diseases. Despite afterload-reducing strategies developed for all diseases, the pulmonary vascular resistance remains highly elevated. Thus preservation of RV function is a therapeutic goal which might have impact on patient survival. We therefore developed an animal model of RV hypertrophy that is independent of changes in afterload by ligation of the pulmonary artery. With this pulmonary arterial banding (PAB) model, parameters of RV remodeling (e.g. cardiomyocyte hypertrophy, interstitial and perivascular remodeling, capillarisation) can be closely monitored and new therapeutic strategies can be tested on RV function. Based on our preliminary data, we now hypothesize that mast cells and their proteases might be involved in RV remodeling in response to an increased hemodynamic load. In order to address the role of mast cells, we will first investigate the origin of these cells in the remodeled RV by systematic morphometric analysis of mast cell number as well as by employing chimeric mice (bone marrow-transplanted mice from enhanced green fluorescence protein (EGFP)-transgenic mice). Second, to gain functional insight in the role of mast cells in RV hypertrophy, mast cell-deficient WBB6F1-KitW/KitW-v mice will be subjected to PAB. RV remodeling will be monitored by high resolution echocardiography, right heart catheterization and histomorphometric techniques. Third, we will investigate the role of chymase, a serine protease expressed exclusively by mast cells, by employing chymase deficient animals (mMCP-4- and mMCP-5-deficient mice). In in vitro experiments, we will co-culture cardiomyocytes and cardiofibroblasts with bone marrow derived cultured mast cells from wild type and chymase deficient animals. In vivo, RV remodeling after PAB will be investigated in mMCP-4- and mMCP-5-deficient mice. Fourth, we will try to reverse deleterious RV remodeling by employing a clinically available mast cell stabilizing agent cromolyn. Fifth, the efficacy of chymase inhibitors like BCEAB will be studied in the PAB model. A better understanding of the role of mast cell chymase in the process of RV remodeling may provide important clues about underlying pathophysiological mechanisms and possible candidate targets which will help us develop novel therapeutic strategies directed specifically to the RV and thus improve survival in patients.

• DFG Programme: Research Grants