Endocrine disruptors effect on inflammatory heart disease

内分泌干​​扰物对炎症性心脏病的影响

• 批准号: 9268276
• 负责人: DeLisa Fairweather
• 金额: $ 16.58万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268276
• 关键词: Endocrine; disruptors; effect; inflammatory; heart

DESCRIPTION (provided by applicant): The long term goal of this project is to determine the effect of endocrine disruptors (EDs), beginning with bisphenol A (BPA), on auto/inflammatory cardiovascular diseases (iCVDs). Myocarditis is an autoimmune iCVD that leads to dilated cardiomyopathy (DCM) and heart failure (HF) and was listed in a recent Lancet report as the 32nd cause of death globally. Autoinflammatory CVDs including myocarditis, DCM, and atherosclerosis occur predominantly in men, who are at an increased risk of developing DCM and HF. The investigators have previously published that testosterone drives myocarditis by increasing mast cells and by activating the inflammasome (i.e. TLR4, caspase-1 and interleukin (IL)-1), resulting in cardiac remodeling, fibrosis and progression to DCM. In contrast, estrogen (E2) decreases myocarditis in female mice by elevating anti- inflammatory immune responses including IL-4/Th2 and regulatory T cells (Treg). Clinical and experimental studies indicate that E2, via the estrogen receptor (ER), mediates cardio-protection against iCVDs in females, while ER signaling has the opposite effect. Since myocarditis and DCM are strongly influenced by sex hormones, ED exposure in utero or as an adult could influence adult autoimmune CVD. To our knowledge no one has examined the potential effect of EDs on myocarditis or DCM. In preliminary studies presented here, the investigators found that a high human relevant exposure of 25 g/L of BPA administered to adult female mice in drinking water significantly increased myocarditis and converted females to a male-like inflammatory profile. ER was significantly decreased in the heart during myocarditis (using qRT-PCR of the whole heart) at this dose of BPA, while ER was significantly increased compared to controls, indicating BPA disregulation of ER signaling in the heart. Based on these findings and the literature on the cardioprotective role of ER, the investigators hypothesize that BPA increases myocarditis in female mice via ER on mast cells. The investigators will investigate the mechanisms of BPA effects on myocarditis and DCM by determining in Aim 1 whether adult exposure to BPA is acting through ER (or other ERs) to increase myocarditis in adult male and female mice, and in Aim 2 by examining the effect of prenatal exposure to BPA on adult disease in male and female offspring (F1). If BPA is activating mast cells to increase iCVD, this study will have a great impact on the understanding of disease pathogenesis.

描述（由申请人提供）：该项目的长期目标是确定以双酚 A (BPA) 为起点的内分泌干扰物 (ED) 对自身/炎症性心血管疾病 (iCVD) 的影响。心肌炎是一种自身免疫性 iCVD，可导致扩张型心肌病 (DCM) 和心力衰竭 (HF)，并在最近的《柳叶刀》报告中被列为全球第 32 位死因。自身炎症性心血管疾病（包括心肌炎、扩张型心肌病和动脉粥样硬化）主要发生在男性中，他们患扩张型心肌病和心力衰竭的风险较高。研究人员此前曾发表文章称，睾酮通过增加肥大细胞和激活炎症小体（即 TLR4、caspase-1 和白细胞介素 (IL)-1）来引发心肌炎，从而导致心脏重塑、纤维化和进展为 DCM。相比之下，雌激素 (E2) 通过增强抗炎免疫反应（包括 IL-4/Th2 和调节性 T 细胞 (Treg)）来减少雌性小鼠的心肌炎。临床和实验研究表明，E2 通过雌激素受体 (ER) 介导女性针对 iCVD 的心脏保护作用，而 ER 信号传导则具有相反的作用。由于心肌炎和 DCM 受性激素的强烈影响，子宫内或成年后接触 ED 可能会影响成人自身免疫性 CVD。据我们所知，没有人研究过 ED 对心肌炎或 DCM 的潜在影响。在此介绍的初步研究中，研究人员发现，成年雌性小鼠在饮用水中摄入 25 g/L BPA 后，人类相关的高暴露量会显着增加心肌炎，并使雌性小鼠的炎症状况转变为与雄性相似的炎症状况。在心肌炎期间（使用整个心脏的 qRT-PCR），在此剂量的 BPA 下，心脏中的 ER 显着降低，而与对照组相比，ER 显着增加，表明 BPA 对心脏中 ER 信号传导的失调。根据这些发现和有关 ER 心脏保护作用的文献，研究人员推测 BPA 通过肥大细胞上的 ER 增加雌性小鼠的心肌炎。研究人员将在目标 1 中确定成人接触 BPA 是否通过 ER（或其他 ER）增加成年雄性和雌性小鼠的心肌炎，并在目标 2 中检查其影响，从而研究 BPA 对心肌炎和 DCM 的影响机制。产前接触 BPA 对雄性和雌性后代成年疾病的影响（F1）。如果 BPA 正在激活肥大细胞以增加 iCVD，那么这项研究将对疾病发病机制的理解产生巨大影响。

项目成果

Sucrose-based cryoprotective storage of extracellular vesicles.

• DOI: 10.1016/j.vesic.2022.100016
• 发表时间: 2022-12
• 期刊: Extracellular vesicle
• 作者: Sierra A. Walker;Irina Davidovich;Yubo Yang;A. Lai;J. P. Goncalves;Vatsal Deliwala;S. Busatto;Shane Shapiro;Na'ama Koifman;C. Salomon;Y. Talmon;Joy Wolfram