Beta3-Adrenergic Receptor & Progression to Heart Failure

Beta3-肾上腺素能受体

• 批准号: 6676457
• 负责人: CHE-PING CHENG
• 金额: $ 32.4万
• 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/6676457
• 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(申请人提供)：我们实验室的初步数据显示，在CHF中，β3-肾上腺素能受体(AR)刺激引起的对正常心肌的心脏抑制作用被放大，从而表明CHF中β3-AR的激活具有直接的不良功能后果。这项资助的目的是：1)表征A3-AR介导的左心室(LV)功能反应在CHF进展前和进展过程中的变化，并评估时间进程，以确定心脏β3-AR在CHF中儿茶酚胺(NE)异常反应中的作用；2)确定改变的β3-AR介导的变力反应的细胞和分子机制。我们将检验假设：[H1]心力衰竭后，心功能对外源性和内源性去甲肾上腺素的反应发生改变，原因是：(I)β_1-AR介导的正性肌力反应减弱，(Ii)β_3-AR介导的左心室抑制和心肌细胞收缩和松弛增强。(3)在CHF运动过程中，由于循环和心肌中NE水平的升高，CHF时β3-AR激活的不良功能效应可能加重，[H2](I)CHF心肌细胞β3-AR表达增加所致，(Ii)伴随着对[Ca~(2+)]i调节的负性调节增强。(Iii)这些效应与GI有关；(Iv)涉及一氧化氮(NO)依赖和NO非依赖的信号转导途径。[H3]慢性A1-AR阻滞剂可以减弱，而β3-AR拮抗剂可以预防左室和心肌细胞功能损害，限制CHF的进展。研究将在慢性仪器清醒犬中进行，包括在起搏诱发静息和运动时的心力衰竭之前和之后，以及在心力衰竭前后从这些动物的左室心肌活检中分离出的心肌细胞。我们将比较心肌细胞β3-AR的mRNA和蛋白水平，以及心肌细胞对β3-AR激动剂或β3-AR拮抗剂的反应、左室和心肌细胞收缩、[Ca2+]i瞬变和钙电流反应。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作用。这些研究将是第一次详细的纵向研究心脏β3-AR基因的表达，以及它在CHF进展前和进展过程中在静息和运动中的功能效应。这些研究对于扩大我们对心脏β-AR调节以及这些受体在CHF中儿茶酚胺异常反应中的作用的认识是必要的。因此，为了解CHF功能损害的进展机制提供了有价值的新见解，并可能有助于CHF的特异性靶向治疗。