Beta3-Adrenergic Receptor & Progression to Heart Failure

Beta3-肾上腺素能受体

• 批准号: 6897937
• 负责人: CHE-PING CHENG
• 金额: $ 32.29万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897937
• 关键词: angiotensin II; beta adrenergic receptor; biological signal transduction; biopsy; catecholamines; congestive heart failure; cyclic AMP; dogs; endothelin; flow cytometry; heart ventricle; nitric oxide; norepinephrine; northern blottings; phase contrast microscopy; polymerase chain reaction; tumor necrosis factor alpha; western blottings

DESCRIPTION (provided by applicant): Preliminary data from our laboratory revealed that in CHF, beta3-adrenergic receptor (AR) stimulation-induced cardiac depression on the normal myocardium is amplified, thus suggesting a direct adverse functional consequence of beta3-ARs activation in CHF. The purpose of this grant is to 1) characterize alterations of a3-AR-mediated functional responses of left ventricle (LV) before and as CHF progresses and assess the time course to establish a contributing causal role of cardiac beta3-AR in the abnormal responsiveness of catecholamine (NE) with CHF; and 2) define the cellular and molecular mechanisms of the altered beta3-AR-mediated inotropic response. We will test Hypothesis: [H1] after CHF, cardiac functional responses to exogenous and endogenous NE are altered due to (i) attenuated beta1-AR-mediated positive inotropic responses and (ii) an enhanced beta3-AR-mediated depression in LV and myocyte contraction and relaxation. (iii) During exercise with CHF, the adverse functional effects of beta3 -AR activation in CHF may be accentuated, due to increases in circulating and myocardial levels of NE, which [H2] (i) results from an increased expression of beta3-AR in CHF myocytes, (ii) accompanied with an enhanced negative modulation on [Ca2+]i regulation. (iii) These effects are linked with Gi, (iv) involving both nitric oxide (NO)-dependent and NO-independent signal transduction pathways. [H3] Chronic a1-AR blocker may attenuate, while beta3-AR antagonist may prevent LV and myocyte functional impairment and limits the progression of CHF. Studies will be conducted in chronically instrumented conscious dogs before and after pacing-induced CHF at rest and during exercise and in myocytes isolated from LV myocardium obtained by biopsy from these same animals before and after CHF. We will compare myocyte beta3-AR mRNA and protein levels; and LV and myocyte contractile, [Ca 2+]i transient, and Ca 2+ current responses to beta3- AR agonist or beta3-AR antagonist before and as CHF progresses and CHF after received three weeks of treatment with beta1-and beta3-AR blockers. The involvement of NO, and inhibitory G proteins in receptor-activated signal transduction will be evaluated by using L-NAME, and PTX. These studies will be the first detailed longitudinal study of the cardiac beta3-AR gene expression, and its functional effects at rest and during exercise before and during the progression of CHF in a clinically relevant higher mammal model of CHF. These studies are necessary to extend our knowledge regarding the cardiac beta-AR regulation and the role of these receptors in the abnormal responsiveness of catecholamine in CHF. Thus, provide valuable new insight into the mechanism of the progression of functional impairment in CHF, and may assist in specifically targeting therapy for CHF.

描述（由申请方提供）：我们实验室的初步数据显示，在CHF中，β 3-肾上腺素能受体（AR）刺激诱导的正常心肌心脏抑制放大，因此表明CHF中β 3-AR激活的直接不良功能后果。本基金的目的是：1）表征CHF进展前和进展时左心室（LV）α 3-AR介导的功能反应的改变，并评估时间进程，以确定心脏β 3-AR在CHF时儿茶酚胺（NE）异常反应中的因果作用; 2）确定β 3-AR介导的变力反应改变的细胞和分子机制。我们将测试假设：[H1] CHF后，由于（i）减弱β 1-AR介导的正性肌力反应和（ii）增强β 3-AR介导的LV和肌细胞收缩和舒张抑制，对外源性和内源性NE的心脏功能反应发生改变。(iii)在CHF运动期间，由于NE的循环和心肌水平升高，CHF中β 3-AR激活的不良功能效应可能加重，[H2]（i）由CHF肌细胞中β 3-AR表达增加引起，（ii）伴随[Ca 2 +]i调节的负性调节增强。(iii)这些作用与Gi有关，（iv）涉及一氧化氮（NO）依赖性和NO非依赖性信号转导途径。[H3]慢性α 1-AR阻滞剂可减轻CHF，而β 3-AR拮抗剂可预防LV和心肌细胞功能损害，并限制CHF的进展。研究将在静息和运动期间起搏诱导CHF前后的慢性仪器清醒犬中进行，并在CHF前后通过活检从这些相同动物的LV心肌中分离的肌细胞中进行。我们将比较心肌细胞β 3-AR mRNA和蛋白水平;左心室和心肌细胞收缩，[Ca 2+]i瞬变和Ca 2+电流对β 3- AR激动剂或β 3-AR拮抗剂的反应，在CHF之前和随着CHF的进展，以及接受β 1-和β 3-AR阻断剂治疗3周后的CHF。将通过使用L-NAME和PTX来评估NO和抑制性G蛋白在受体激活的信号转导中的参与。这些研究将是第一个详细的纵向研究心脏β 3-AR基因的表达，其功能的影响，在休息和运动之前和期间的CHF进展中的临床相关的高等哺乳动物模型的CHF。这些研究是必要的，以扩大我们的知识，心脏β-AR的调节和这些受体的作用，在儿茶酚胺的异常反应性在CHF。因此，提供了有价值的新的见解，CHF的功能障碍的进展机制，并可能有助于CHF的特异性靶向治疗。