Aldosteronism: An Immunostimulatory State

醛固酮增多症：一种免疫刺激状态

基本信息

批准号：
7273690
负责人：
KARL T WEBER
金额：
$ 34.61万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-17 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7273690
关键词：
ATP phosphohydrolase Acetylcysteine Address Aldosterone Aldosterone Receptors Animals Anorexia Antibodies Antioxidants Apoptotic Appearance B-Lymphocytes Blood Vessels CCL2 gene Cachexia Cardiac Cardiac Myocytes Cations Cells Cessation of life Characteristics Cholinergic Receptors Chronic Clinical Congestive Congestive Heart Failure Connective Tissue Coronary artery Development Diet Elevation Erythrocytes Event Excretory function Failure Fc Receptor Food Functional disorder Gene Expression Gene Expression Profile Gene Proteins Genes Health Heart Heart Atrium Heart failure Hormones Host Defense Hyperaldosteronism Immune Inflammation Inflammation Mediators Inflammatory Injury Intercellular adhesion molecule 1 Interleukin 2 Receptor Interleukin-3 Receptor Interleukin-6 Invaded Left atrial structure Lesion Lymphocyte Mass Spectrum Analysis Mediating Messenger RNA Mineralocorticoid Receptor Modeling Molecular Monitor NADPH Oxidase Na(+)-K(+)-Exchanging ATPase Necrosis Numbers Onset of illness Oxidation-Reduction Oxidative Stress Oxidative Stress Induction Oxis Pathologic Pathology Pathology Report Pathway interactions Pattern Peripheral Blood Mononuclear Cell Peroxidase Peroxidases Peroxides Phenotype Physicians Plant Roots Plasma Principal Investigator Production Protein Tyrosine Phosphatase Proteins Proteome Pump Rattus Relative (related person)Renin-Angiotensin-Aldosterone System Rodent Role Signs and Symptoms Site Sodium Chloride Spironolactone Staging Standards of Weights and Measures Stress Substance P Substance P Receptor Supplementation Syndrome Testing Therapeutic Intervention Up-Regulation Ventricular Ventricular Dysfunction Water Weight Gain cytokine in vivo mRNA Expression macrophage monocyte peroxiredoxin I pre-clinical prevent programs protective effect protein expression receptor receptor expression response wasting

项目摘要

DESCRIPTION (provided by applicant): Irrespective of its origins, asymptomatic (preclinical) ventricular dysfunction eventuates in: activation of the circulating renin-angiotensin-aldosterone system with symptomatic congestive heart failure (CHF) and a systemic illness with elevated plasma cytokines, anorexia & wasting (clinical); and progressive cardiac remodeling (pathologic). Cellular & molecular pathways involved at each stage remain to be elucidated. We use 4wk aldosterone (ALDO) treatment in rats and examine preclinical (wks 1-2), clinical (wk3), and clinicopathologic (wk4) stages. At vascular and nonvascular sites of injury that first appear in both atria & ventricles at wk4, evidence of NADPH oxidase expression and activity is found in invading immune ceils, together with activation of NFkB and expression of genes encoding for host defenses. Clinical and pathologic stages are prevented by co-treatment with spironolactone (Spi) or N-acetylcysteine (NAC). Herein we hypothesize this proinflammatory cardiac phenotype is a result of an immunostimulatory state found in peripheral blood mononuclear cells (PBMC) activated by oxi/nitrosative stress and induced by PBMC (Mg2+)i deficiency. Cardiac pathology, reported by others at wk3 of dietary Mg2+ deficiency, is likewise preceded by PBMC activation at wkl and is prevented by antioxidant or receptor antagonist (L-703,606) to substance P, a neurogenic mediator of inflammation. We examined the PBMC molecular phenotype (MP), including all expressed genes and proteins, obtained weekly from rats treated with ALDO/salt for 4wks. Changes in mRNA expression revealed an early (wk1) reduction in ATPase-dependent genes and a progressive development of oxi/nitrosative stress, and an upregulation of antioxidant defenses sustained over 4wks. B lymphocyte responses, including upregulation of antibody genes, appear from wkl on. Changes in protein expression identified early reduction in Mg 2+-dependent Ca 2+ pump and peroxiredoxin-I. Thus, the transcriptome and proteome of PBMC serve as early markers of stress and the systemic immunostimulatory state heralding the onset of illness and cardiac pathology. Specific Aims: 1) to monitor MP in PBMC activated in vivo and to determine the role of ALDO and Mg2+ by comparing responses to ALDO/salt plus Mg 2+ in a) standard (stan) or b) deficient (def) chows, c) with stan chow+Mg 2+ supplements, or d) Mg 2+ def chow alone (no ALDO); 2) to monitor MP of PBMC activated in vivo and determine genes & proteins involved in the appearance of illness and cardiac pathology by addressing the protective effects of Spi, NAC, or L-703,606; and 3) to determine the type(s) of PBMC necessary for the induction of the proinflammatory cardiac phenotype that appears in response to ALDO/salt/stan chow treatment. This study may identify preclinical markers that predict the development of CHF and cardiac remodeling, and may produce treatment strategies.

描述（由申请人提供）：无论其起源如何，无症状（临床前）心室功能障碍最终会导致：循环肾素-血管紧张素-醛固酮系统激活，伴有症状性充血性心力衰竭（CHF）以及血浆细胞因子升高、厌食和消耗（临床）；和进行性心脏重塑（病理性）。每个阶段涉及的细胞和分子途径仍有待阐明。我们对大鼠使用 4 周醛固酮 (ALDO) 治疗，并检查临床前（第 1-2 周）、临床（第 3 周）和临床病理（第 4 周）阶段。在第 4 周首次出现在心房和心室的血管和非血管损伤部位，在入侵的免疫细胞中发现了 NADPH 氧化酶表达和活性的证据，以及 NFkB 的激活和编码宿主防御的基因的表达。通过与螺内酯 (Spi) 或 N-乙酰半胱氨酸 (NAC) 联合治疗可以预防临床和病理阶段。在此，我们假设这种促炎性心脏表型是由氧化/亚硝化应激激活并由 PBMC (Mg2+)i 缺乏诱导的外周血单核细胞 (PBMC) 中发现的免疫刺激状态的结果。其他人在第 3 周报告膳食 Mg2+ 缺乏症时出现的心脏病理学，同样在第 1 周时 PBMC 激活之前发生，并且可通过抗氧化剂或 P 物质受体拮抗剂 (L-703,606) 来预防，P 物质是炎症的神经源性介质。我们检查了 PBMC 分子表型 (MP)，包括所有表达的基因和蛋白质，每周从接受 ALDO/盐治疗 4 周的大鼠中获得。 mRNA 表达的变化揭示了 ATP 酶依赖性基因的早期（第 1 周）减少和氧化/亚硝化应激的逐渐发展，以及持续超过 4 周的抗氧化防御的上调。 B淋巴细胞反应，包括抗体基因的上调，从第1周开始出现。蛋白质表达的变化表明 Mg 2+ 依赖性 Ca 2+ 泵和过氧化还原蛋白-I 的早期减少。因此，PBMC 的转录组和蛋白质组可作为应激和全身免疫刺激状态的早期标记，预示着疾病和心脏病的发作。具体目标：1) 监测体内激活的 PBMC 中的 MP，并通过比较 a) 标准 (stan) 或 b) 缺乏 (def) 食物、c 中对 ALDO/盐加 Mg 2+ 的反应来确定 ALDO 和 Mg2+ 的作用) 与 stan chow+Mg 2+ 补充剂，或 d) 单独 Mg 2+ def Chow（无 ALDO）； 2) 通过解决 Spi、NAC 或 L-703,606 的保护作用，监测体内激活的 PBMC MP，并确定与疾病和心脏病出现相关的基因和蛋白质； 3) 确定诱导促炎性心脏表型所需的 PBMC 类型，该促炎性心脏表型是对 ALDO/盐/斯坦周治疗的反应。这项研究可能会确定预测 CHF 和心脏重塑发展的临床前标志物，并可能产生治疗策略。