The Role of Vascular MR-Regulated Genes in Vascular Function and Disease

血管 MR 调控基因在血管功能和疾病中的作用

基本信息

批准号：
10594445
负责人：
Iris Z Jaffe
金额：
$ 78.45万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594445
关键词：
Age Aging Aldosterone Anti-Inflammatory Agents Aorta Apolipoprotein E Atherosclerosis Automobile Driving Biological Assay Blood Pressure Blood Vessels Bromodeoxyuridine Cardiovascular Diseases Cardiovascular system Cause of Death Cell Adhesion Cell Adhesion Molecules Cell Communication Cell Line Cell Nucleus Cell physiology Cells Clinical Data Disease E-Selectin Elderly Endothelial Cells Estrogen Receptor alpha Estrogens Female Functional disorder Genes Genetic Genetic Transcription Genomics Heart Diseases Heart failure Histology Hormones Human ICAM1 gene Immune Immune system In Vitro Inflammation Inflammatory Ischemia Kidney Knockout Mice Leukocyte Rolling Leukocytes Ligands Link Macrophage Mediating Medical Menopause Mesentery Metabolic syndrome Methods Mineralocorticoid Receptor Modeling Molecular Mus Myelogenous Myeloid Cells Myocardial Infarction Nitric Oxide Obesity Outcome Persons Phenotype Population Premenopause Production Reagent Receptor Activation Receptor Inhibition Regulation Resistant Hypertension Risk Role Rupture Scaffolding Protein Sex Differences Signal Transduction Steroid Receptors Stroke T-Cell Activation T-Cell Proliferation T-Lymphocyte T-Lymphocyte Subsets Testing Thinness Thrombosis Tissues Woman antagonist biobank blood pressure control blood pressure regulation cardiovascular risk factor cytokine demographics heart disease risk high risk human female in vivo innovation intravital microscopy male men monocyte mortality mouse model mutant non-genomic novel obese person prevent receptor recruit response sex tool trafficking transcription factor vascular inflammation

项目摘要

The mineralocorticoid receptor (MR) is an aldosterone (Aldo)-activated receptor that regulates gene transcription (genomic) and cellular signaling (non-genomic) to control cell functions and regulate blood pressure (BP). MR activation is increased in resistant hypertension, obesity, heart failure and the elderly. Increased Aldo predicts high risk of myocardial infarction (MI) and stroke and MR antagonists are protective out of proportion to BP lowering, supporting kidney-independent mechanisms. MI and stroke are caused by rupture and thrombosis of inflamed atherosclerotic (athero) plaques. Women are protected from MI and stroke relative to men until menopause thereby implicating another hormone, estrogen (E2), while obese women with metabolic syndrome lose premenopausal protection with rising mortality in this growing demographic. We recently showed that MR in endothelial cells (EC) contributes to vascular inflammation in athero in male mice by inducing leukocyte recruitment to vessels and expression of ICAM1 and E-selectin (E-sel) and that this is prevented in females. We also showed that estrogen receptor alpha (ERa) interacts with the MR in ECs, blocking MR regulation of ICAM1 and that EC-MR-KO protects obese females from EC dysfunction. New data shows that ICAM1 expression is decreased in primary human ECs from females vs males and this is reversed in obese females; that EC-MR inhibits the non-genomic effect of E2 to increase nitric oxide (NO); and that myeloid (My)-MR-KO decreases plaque size and inflammation in ApoE-KO mice, leukocyte rolling by intravital microscopy (IVM), and macrophage expression of EC adhesion ligands. Based on these data, we propose to test the hypothesis that EC- and My-MR coordinate vascular inflammation in athero and that females are protected by genomic and non- genomic interactions between MR and ERa. To test this, we have created innovative reagents and methods including mice with EC-specific deletion of MR, ERa or both and myeloid-specific deletion of MR, each crossed to athero-prone genetic mouse models; a mesenteric IVM assay to test sex differences in leukocyte traficking; EC lines with ERa functional mutants; and a biobank of age matched male and female human aortic ECs. Using these tools we propose 2 specific aims, each using in vitro and in vivo approaches: SA1 explores the genomic and non-genomic mechanisms by which MR and ERa interact in ECs to regulate leukocyte recruitment and plaque inflammation and how this mediates sex differences; SA2 determines the role of My-MR in immune cell trafficking, plaque macrophage phenotype, and sex-differences in myeloid-T cell interactions. Using these innovative models, methods, and reagents tailored to study sex-differences, this proposal investigates the novel concept that EC- and My-MR coordinate vascular and immune cell responses to induce leukocyte recruitment and vascular inflammation in athero. Completion of the aims will identify mechanisms underlying increased cardiovascular (CV) risk in growing populations with elevated MR activity and for sex differences in CV disease.

矿物皮质激素受体（MR）是醛固酮（Aldo）激活的受体，可调节基因转录（基因组）和细胞信号传导（非基因组），以控制细胞功能并调节血压（BP）。先生耐药性高血压，肥胖，心力衰竭和老年人的激活增加。增加了Aldo的预测心肌梗塞（MI）和中风和MR拮抗剂的高风险与BP不成比例降低，支持肾脏独立的机制。 MI和中风是由破裂和血栓形成引起的动脉粥样硬化（Athero）斑块。女性免受男性的MI和中风，直到更年期，从而暗示另一种激素，即雌激素（E2），而肥胖的女性代谢综合征在这种日益增长的人群中，由于死亡率上升而失去绝经前的保护。我们最近表明先生在内皮细胞（EC）中，通过诱导白细胞来导致雄性小鼠的血管炎症招募ICAM1和E-选择素（E-SEL）的血管和表达，并且在女性中可以预防。我们还表明雌激素受体α（ERA）与EC中的MR相互作用，阻止了ICAM1的MR调节 EC-MR-KO可保护肥胖女性免受EC功能障碍。新数据表明ICAM1表达是女性与雄性的原发性EC减少，肥胖女性逆转。那个EC-MR 抑制E2的非基因组效应增加一氧化氮（NO）；并且髓样（我的）-mr-ko减少 APOE-KO小鼠的斑块大小和炎症，白细胞通过插入显微镜（IVM）滚动，并 EC粘附配体的巨噬细胞表达。基于这些数据，我们建议检验以下假设。 Athero中的EC和My-MR坐标血管炎症，并且女性受到基因组和非基因组的保护 MR和ERA之间的基因组相互作用。为了测试这一点，我们创建了创新的试剂和方法包括具有MR，ERA或ERA的特定于EC特异性缺失的小鼠，MR都越过到动脉粥样硬化的遗传小鼠模型；一种肠系膜IVM测定法测试白细胞转移的性别差异；具有ERA功能突变体的EC线；以及年龄的生物库与男性和女性主动脉EC相匹配。使用这些工具我们提出了2个特定目标，每个目标都使用体外和体内方法：SA1探索基因组以及MR和ERA在EC中相互作用以调节白细胞募集和的非基因组机制斑块炎症以及这如何介导性别差异； SA2确定My-MR在免疫细胞中的作用髓样-T细胞相互作用中的运输，斑块巨噬细胞表型和性别差异。使用这些该提案研究了新小说 EC和MY-MR坐标的概念是诱导白细胞募集的血管和免疫细胞反应和动脉炎的血管炎症。目的的完成将确定增加的机制增加在MR活动升高和CV疾病中的性别差异的人群中，心血管（CV）的风险（CV）风险。