Role of Aldosterone and Adiponectin in Inter-Tissue Communication in Diastolic He

醛固酮和脂联素在舒张期肝组织间通讯中的作用

基本信息

批准号：
8583804
负责人：
Flora Sam
金额：
$ 38.96万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8583804
关键词：
Accounting Address Adenovirus Vector Adipocytes Adipose tissue Aldosterone Angiotensin II Angiotensins Animal Model Anti-Inflammatory Agents Anti-inflammatory Antihypertensive Agents Attenuated Autophagocytosis Biometry Calcium Cardiac Cardiac Myocytes Cardiovascular Physiology Cardiovascular system Cell Communication Cells Clinical Coculture Techniques Collagen Communication Development Diastolic Hypertension Diastolic heart failure Disease Progression Dose EFRAC Extracellular Matrix Fatty acid glycerol esters Functional disorder Heart Diseases Heart failure Human Hypertension Incidence Individual Inflammatory Investigation Left Left Ventricular Hypertrophy Link Matrix Metalloproteinases Measurement Measures Mediating Modeling Molecular Biology Morbidity - disease rate Mus Obesity Pathogenesis Pathologic Patients Pharmaceutical Preparations Phosphorylation Plasma Proteins Play Prevalence Proteins Relative (related person)Research Personnel Resistance Risk Factors Role Signal Transduction Specialist Symptoms Systolic heart failure Testing Tissues Transgenic Mice Ventricular Work abdominal fat adipokines adiponectin blood pressure regulation cytokine experience molecular phenotype mortality mouse model overexpression public health relevance research study stem subcutaneous translational study

项目摘要

DESCRIPTION (provided by applicant): Diastolic heart failure (HF), also known as "heart failure-preserved-ejection fraction", accounts for up to 50% of all HF presentations, but unlike systolic HF, therapies remain ineffective despite increasing morbidity and mortality. This stems, in part, from a lack of mechanistic understanding about diastolic HF. Hypertension is the major cause of diastolic HF and the prevalence of diastolic HF is projected to increase as the incidence of hypertension rises. Obese individuals also have a high incidence of poorly controlled blood pressure and diastolic HF. This raises the possibility that factors secreted by fa may play a role in hypertension-related diastolic HF. Although a causal link exists between aldosterone and arterial hypertension, increasing evidence demonstrates a link between aldosterone and obesity with evidence that adipocytes, in addition to secreting adiponectin (APN), may release secreted factors that stimulate aldosterone release independent of angiotensin-II. APN, an adipose-derived plasma protein, exerts anti-inflammatory and anti-hypertrophic effects by modulating phosphorylation signals in cardiovascular cells and is implicated in the development of hypertension and systolic HF. APN levels are decreased in obesity and hypertension, but elevated in systolic HF, also known as "heart failure-reduced-ejection fraction". Conversely aldosterone is increased in obesity, hypertension and in HF. Recently our lab showed that hypoadiponectinemia in hypertension-induced diastolic HF exacerbates left ventricular hypertrophy, diastolic dysfunction and diastolic HF. We seek to examine the contribution of APN to the relative increase in aldosterone in diastolic HF. The broad objective of this proposal is that dysregulation between aldosterone and APN contributes to the pathogenesis of diastolic HF and adverse cardiac remodeling. To our knowledge this conceptual model has not been tested nor hypothesized. We will test the hypothesis that an alteration in APN levels facilitates an increase in aldosterone increasing the propensity to diastolic HF and diastolic dysfunction. To address this hypothesis we will test the following aims: Aim 1) to investigate if dysregulation of APN levels are associated with alterations in aldosterone levels in human diastolic HF. Hypothesis 1. Aldosterone and APN levels are elevated in stable diastolic HF patients and are associated with left ventricular (LV) diastolic dysfunction measurements. Hypothesis 2. Changes in aldosterone and APN levels (between acutely, decompensated and stable, ambulatory diastolic HF) are associated with disease progression (as determined by echocardiographic derived measures of LV diastolic dysfunction) in diastolic HF. Aim 2) To determine if APN ameliorates the transition from hypertension to diastolic dysfunction and diastolic HF in a mouse model of diastolic HF and dysfunction. Aim 3) To investigate the role of autophagy in diastolic dysfunction in cardiac myocytes and the signaling mechanisms involved in cell-to-cell communication between cardiac myocytes and adipocytes in diastolic HF.

描述（由申请人提供）：舒张性心力衰竭 (HF)，也称为“射血分数保留的心力衰竭”，占所有心力衰竭表现的 50%，但与收缩性心力衰竭不同，尽管发病率和死亡率不断增加，但治疗仍然无效。死亡。这在一定程度上是由于缺乏对舒张期心力衰竭的机制了解。高血压是舒张性心力衰竭的主要原因，预计舒张性心力衰竭的患病率会随着高血压发病率的上升而增加。肥胖者血压控制不佳和舒张性心力衰竭的发生率也很高。这提出了 fa 分泌的因子可能在高血压相关的舒张性心力衰竭中发挥作用的可能性。尽管醛固酮和动脉高血压之间存在因果关系，但越来越多的证据表明醛固酮和肥胖之间存在联系，有证据表明脂肪细胞除了分泌脂联素（APN）外，还可能释放不依赖于血管紧张素-II 的刺激醛固酮释放的分泌因子。 APN 是一种脂肪来源的血浆蛋白，通过调节心血管细胞中的磷酸化信号发挥抗炎和抗肥厚作用，并与高血压和收缩性心力衰竭的发生有关。 APN 水平在肥胖和高血压中降低，但在收缩性心力衰竭（也称为“心力衰竭射血分数降低”）中升高。相反，肥胖、高血压和心力衰竭时醛固酮会增加。最近我们的实验室发现，高血压引起的舒张期心力衰竭中的低脂联素血症会加剧左心室肥大、舒张功能障碍和舒张期心力衰竭。我们试图研究 APN 对舒张期心力衰竭中醛固酮相对增加的贡献。该提案的总体目标是醛固酮和 APN 之间的失调导致舒张期心力衰竭和不良心脏重塑的发病机制。据我们所知，这个概念模型尚未经过测试或假设。我们将检验这样的假设：APN 水平的改变会促进醛固酮的增加，从而增加舒张性心力衰竭和舒张功能障碍的倾向。为了解决这个假设，我们将测试以下目标：目标 1) 研究 APN 水平失调是否与人类舒张性心力衰竭中醛固酮水平的变化相关。假设 1. 舒张期稳定的心力衰竭患者中醛固酮和 APN 水平升高，并且与左心室 (LV) 舒张功能障碍测量相关。假设 2. 醛固酮和 APN 水平的变化（在急性、失代偿和稳定、动态舒张期心力衰竭之间）与舒张期心力衰竭的疾病进展（通过超声心动图测量左室舒张功能障碍确定）相关。目标 2) 确定 APN 是否可以改善舒张性心力衰竭和功能障碍小鼠模型中从高血压到舒张功能障碍和舒张性心力衰竭的转变。目的 3) 研究自噬在心肌细胞舒张功能障碍中的作用以及舒张期心力衰竭心肌细胞与脂肪细胞之间细胞间通讯的信号机制。