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

• 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
• 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

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(申请人提供)：舒张性心力衰竭(HF)，也被称为“心力衰竭-保留-射血分数”，占所有HF表现的50%，但与收缩期HF不同，尽管发病率和死亡率不断上升，治疗仍然无效。这在一定程度上是由于缺乏对舒张期心衰的机械性了解。高血压是舒张性心衰的主要原因，随着高血压发病率的增加，舒张性心衰的患病率预计会增加。肥胖者的血压控制不良和舒张性心衰的发生率也很高。这增加了由FA分泌的因子可能在高血压相关的舒张性心衰中发挥作用的可能性。虽然醛固酮与动脉高血压之间存在因果联系，但越来越多的证据表明，醛固酮与肥胖之间存在联系，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大作用，参与高血压和收缩期心衰的发生发展。APN水平在肥胖和高血压患者中降低，但在收缩期心衰患者中升高，也称为“心力衰竭射血分数降低”。相反，在肥胖、高血压和心力衰竭患者中，醛固酮水平会增加。最近我们的实验室发现，高血压引起的舒张性心衰患者的低脂联素血症会加重左室肥厚、舒张期功能障碍和舒张期心力衰竭。我们试图研究APN对舒张期心衰时相对升高的醛固酮的贡献。这项建议的主要目的是，醛固酮和APN之间的失调有助于舒张性心衰和不利的心脏重构的发病。据我们所知，这一概念模型既没有经过检验，也没有被假设。我们将检验这一假设，即APN水平的改变促进了醛固酮的增加，增加了舒张性心衰和舒张期功能障碍的倾向。为了解决这一假设，我们将测试以下目标： 目的1)探讨APN水平异常是否与舒张期心力衰竭患者的醛固酮水平改变有关。假设1：稳定的舒张期心衰患者的醛固酮和APN水平升高，并与左心室(LV)舒张期功能不全的测量结果相关。假设2：舒张性心衰患者的心力衰竭时，醛固酮和APN水平的变化(急性期、失代偿期和稳定期之间)与疾病进展有关(由超声心动图测量左室舒张功能不全来确定)。目的2)研究APN能否改善舒张性心衰小鼠高血压向舒张期心功能不全和舒张期心功能不全的转变。目的3)探讨自噬在舒张性心衰心肌细胞功能障碍中的作用及其参与心肌细胞与脂肪细胞之间细胞间通讯的信号机制。