Right Heart Function in Health and Chronic Lung Disease

健康与慢性肺病中的右心功能

• 批准号: 8696775
• 负责人: Anthony J. BAKER
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696775
• 关键词: Adrenergic Agonists; Adrenergic Receptor; Affect; Agonist; Applications Grants; Bleomycin; Cardiovascular system; Catecholamines; Cause of Death; Chronic lung disease; Contractile Proteins; Disease; Dose; Down-Regulation; Failure; Family suidae; Functional disorder; Funding; Grant; Health; Heart; Heart failure; Human; Hypertrophy; In Vitro; Knock-out; Knockout Mice; Knowledge; Left; Left ventricular structure; Life; Lung; Mediating; Microfilaments; Modeling; Morbidity - disease rate; Mus; Myosin Light Chain Kinase; Norepinephrine; Outcome; Patients; Phenylephrine; Phosphorylation; Physiological; Physiology; Pulmonary Fibrosis; Pulmonary Hypertension; Pump; Receptor Signaling; Regulation; Reporting; Resources; Right ventricular structure; Role; Sampling Studies; Side; Signal Transduction; Specificity; Symptoms; Testing; United States National Institutes of Health; Up-Regulation; Veterans; alpha-1 adrenergic receptors; base; clinically significant; heart function; human disease; improved; in vivo; loss of function; mortality; mutant; myosin light chain 2; novel; novel strategies; novel therapeutic intervention; outcome forecast; pressure; response; targeted treatment

DESCRIPTION (provided by applicant): Failure of the right ventricle (RV) is a prevalent cause of cardiovascular morbidity and mortality. However, RV failure is relatively understudied and poorly understood, thus there is a need for greater understanding of the pathophysiology of RV failure. We reported that inotropic regulation is distinctly different in the RV than the LV. Moreover, our new preliminary studies suggest that inotropic regulation of the RV is affected very differently in heart failure compared to the LV. We found that in failing RV the inotropic response to norepinephrine (NE, a mixed 1/2 agonist) was appreciably increased, despite downregulation of 2-responses; thus, suggesting upregulation of responses to alpha-1 adrenergic receptors (11-ARs). Consistent with this, we recently reported that in failing RV the inotropic response to 11-AR agonism is increased. Mechanistically, we found that myosin light chain kinase (MLCK), which is activated by 11-ARs, is increased in the failing RV. Increased MLCK might contribute to increased inotropic responses in the failing RV by causing increased phosphorylation of the contractile protein myosin light chain-2 (MLC2), and consequently, increased myofilament Ca2+ sensitivity. Based on preliminary results, we will test two hypotheses: 1) In RV failure, increased 11-AR inotropy compensates for 2-AR downregulation to mediate increased inotropic responses to the natural catecholamine NE; 2) In RV failure, therapies to further increase 11-AR signaling will improve RV function and outcomes. This project has a "mechanism aim" to determine the basis of increased inotropic responses in failing RV; and a "translational aim" to study a new therapeutic approach for RV failure. We will study the RV-specific model of bleomycin-induced pulmonary fibrosis, which leads to pulmonary hypertension and RV failure. Aim 1. Determine the role of 11-AR signaling in mediating an increased RV inotropic response to NE in RV failure. For increased RV responses to NE in a RV-specific heart failure model, we will determine the roles of: 11-ARs, 11-AR subtypes (using knockouts), MLCK-induced phosphorylation of MLC2 (using a loss of function mutant), and increased myofilament Ca2+ sensitivity. We will determine the relevance to human disease by studying samples from failing and nonfailing human hearts using the "UCSF Living Heart Resource" that was recently funded by a NIH Challenge Grant to procure failing and nonfailing human hearts for physiologic study (the PI is Co-PI on this Challenge Grant). Aim 2. Determine if therapeutically increased 11A-AR subtype signaling has a beneficial effect on RV function and outcomes in RV failure. Using an RV-specific heart failure model, we will chronically treat mice with a low dose of the 11A-AR subtype-specific agonist A61603. We will determine if A61603 improves RV function and outcomes in RV failure, and determine the mechanisms involved. To determine the 11A-AR- specificity of improvements with A61603, we will determine if the 11A-AR is necessary by using knockout mice lacking the 11A-AR subtype; and determine if the 11A-AR is sufficient by using mice expressing only the 11A-AR. These studies will be significant for understanding and treating human disease. In heart failure, where catecholamines are elevated, upregulation of RV inotropic responses might help the RV adapt to increased pulmonary pressures. Moreover, in heart failure, inotropic regulation of the RV (increased inotropy) differs fundamentally from the LV (decreased inotropy), suggesting that new approaches for treating RV failure could be tailored to the distinctive physiology of the RV. This project will explore such a new approach.

描述（由申请人提供）： 右心室（RV）衰竭是心血管疾病发病率和死亡率的常见原因。然而，右心室衰竭的研究相对不足，了解甚少，因此有必要更好地了解右心室衰竭的病理生理学。我们报道了右心室的变力性调节与左心室明显不同。此外，我们新的初步研究表明，心力衰竭时右心室的变力性调节与左心室相比受到非常不同的影响。我们发现，在失败的RV的正性肌力反应去甲肾上腺素（NE，混合1/2激动剂）明显增加，尽管下调2-反应，因此，建议上调反应的α-1肾上腺素能受体（11-AR）。与此相一致，我们最近报道，在失败的RV的变力反应11-AR激动剂增加。从机制上讲，我们发现，肌球蛋白轻链激酶（MLCK），这是激活11-AR，是增加失败的RV。MLCK增加可能通过引起收缩蛋白肌球蛋白轻链-2（MLC 2）磷酸化增加，从而增加肌丝Ca 2+敏感性，从而增加衰竭RV的变力性反应。 基于初步结果，我们将检验两个假设：1）在RV衰竭中，增加的11-AR正性肌力补偿2-AR下调，以介导对天然儿茶酚胺NE的正性肌力反应增加; 2）在RV衰竭中，进一步增加11-AR信号传导的疗法将改善RV功能和结局。 该项目的“机制目标”是确定RV衰竭时变力性反应增加的基础;“转化目标”是研究RV衰竭的新治疗方法。我们将研究博来霉素诱导的肺纤维化的RV特异性模型，其导致肺动脉高压和RV衰竭。目标1。确定11-AR信号在RV衰竭时介导RV对NE的变力性反应增加中的作用。对于RV特异性心力衰竭模型中RV对NE的反应增加，我们将确定以下因素的作用：11-AR、11-AR亚型（使用敲除）、MLCK诱导的MLC 2磷酸化（使用功能缺失突变体）和肌丝Ca 2+敏感性增加。我们将通过使用“加州大学旧金山分校活体心脏资源”研究衰竭和非衰竭人类心脏的样本来确定与人类疾病的相关性，该资源最近由NIH挑战补助金资助，以获取衰竭和非衰竭人类心脏用于生理研究（PI是该挑战补助金的联合PI）。目标二。确定治疗性增加的11 A-AR亚型信号传导是否对RV功能和RV衰竭的结局具有有益影响。使用RV特异性心力衰竭模型，我们将用低剂量的11 A-AR亚型特异性激动剂A61603长期治疗小鼠。我们将确定A61603是否改善RV功能和RV衰竭的结局，并确定相关机制。为了确定A61603改善的11 A-AR特异性，我们将通过使用缺乏11 A-AR亚型的敲除小鼠来确定11 A-AR是否是必要的;并通过使用仅表达11 A-AR的小鼠来确定11 A-AR是否足够。 这些研究对于了解和治疗人类疾病具有重要意义。在心脏衰竭时，其中儿茶酚胺升高，RV变力性反应的上调可能有助于RV适应增加的肺动脉压。此外，在心力衰竭中，RV的变力性调节（增加的变力性）与LV（降低的变力性）根本不同，这表明用于治疗RV衰竭的新方法可以针对RV的独特生理学而定制。本项目将探索这样一种新方法。