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

肥大细胞在压力超负荷引起的右心室重塑和衰竭中的作用

• 批准号: 280298313
• 负责人: Professor Dr. Ralph Schermuly
• 金额: --
• 依托单位: Biomedizinisches Forschungszentrum Seltersberg (BFS)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280298313?language=en
• 关键词: Role; mast; cells; pressure; overload

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.

几种类型的先天性心脏缺陷、肺血管疾病和左心疾病伴肺静脉压升高可导致右心室后负荷增加和右心肥厚。虽然许多研究都集中在左心肥厚的机制上，但关于右心室（RV）重塑过程的信息有限。最重要的是，RV的表现决定了先天性心脏病、肺动脉高压、晚期左心衰竭甚至稳定性心血管疾病患者的预后。尽管为所有疾病开发了后负荷减少策略，但肺血管阻力仍然高度升高。因此，保存右心室功能是一个可能影响患者生存的治疗目标。因此，我们开发了一种独立于肺动脉结扎后负荷变化的右心室肥大动物模型。利用这种肺动脉带（PAB）模型，可以密切监测心室重构的参数（如心肌细胞肥大、间质和血管周围重构、毛细血管化），并可以测试新的治疗策略。根据我们的初步数据，我们现在假设肥大细胞及其蛋白酶可能参与右心室重构，以应对增加的血流动力学负荷。为了解决肥大细胞的作用，我们将首先通过对肥大细胞数量的系统形态计量学分析以及嵌合小鼠（从增强绿色荧光蛋白（EGFP）转基因小鼠移植骨髓的小鼠）来研究这些细胞在重构RV中的来源。其次，为了了解肥大细胞在RV肥大中的功能作用，肥大细胞缺陷的WBB6F1-KitW/KitW-v小鼠将接受PAB治疗。右心室重构将通过高分辨率超声心动图、右心导管和组织形态学技术进行监测。第三，我们将通过使用乳糜酶缺陷动物（mMCP-4和mmcp -5缺陷小鼠）来研究乳糜酶的作用，乳糜酶是一种仅由肥大细胞表达的丝氨酸蛋白酶。在体外实验中，我们将心肌细胞和成纤维细胞与野生型和乳糜酶缺陷动物的骨髓来源的肥大细胞共同培养。在体内，将在mMCP-4和mmcp -5缺陷小鼠中研究PAB后的RV重塑。第四，我们将尝试通过使用临床可用的肥大细胞稳定剂色莫利来逆转有害的左室重塑。第五，在PAB模型中研究chymase inhibitors如BCEAB的疗效。更好地了解肥大细胞切酶在右心室重塑过程中的作用可能为潜在的病理生理机制和可能的候选靶点提供重要线索，这将有助于我们开发专门针对右心室的新型治疗策略，从而提高患者的生存率。