Systolic Cardiac Function in Obesity and Exercise

肥胖和运动中的心脏收缩功能

• 批准号: 6638653
• 负责人: JOAN F CARROLL
• 金额: $ 26.93万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6638653
• 关键词: G protein; adenylate cyclase; beta adrenergic receptor; calcium transporting ATPase; cholera toxin; collagen; cyclic AMP; enzyme activity; exercise; heart contraction; heart pharmacology; hemodynamics; hydralazine; isoproterenol; laboratory rabbit; obesity; pertussis toxin; sarcoplasmic reticulum; ventricular hypertrophy

DESCRIPTION (Applicant's abstract): The broad objectives of the proposed research are to determine mechanisms for reduced responsiveness to cardiac Beta-adrenergic stimulation in obesity and mechanisms whereby exercise training during the development of obesity may attenuate these effects. We hypothesize that obesity causes alterations in hemodynamics, cardiac hypertrophy, cardiac collagen, hormonal profile, and systolic function that are independent of hypertension. To test this hypothesis, we will compare lean rabbits with obese rabbits that develop hypertension along with obesity, and obese rabbits in which blood pressure will be controlled at pre-obese values using oral Hydralazine. We will use acute and chronic (telemetry) measurement of heart rate and blood pressure, as well as colored microspheres, to study hemodynamics. We will use western blotting techniques, blood sampling, wet and dry cardiac weights, and the Langendorff isolated heart preparation to analyze collagen, hormonal profile, cardiac hypertrophy, and systolic function. We also hypothesize that decreased cardiac responsiveness to Beta-adrenergic stimulation in obesity is due to abnormalities both at the cardiac Beta-receptor and in the G-coupled protein cascade leading to cAMP formation and calcium release from the sarcoplasmic reticulum. We will use appropriate assay and western blotting techniques to provide an analysis of the role of beta-receptor and post-receptor components such as Beta-receptor/Gs coupling, Gs stimulation of adenylate cyclase; formation of cAMP; activation of PKA, and sarcoplasmic reticulum calcium handling in contributing to cardiac abnormalities in obesity. We hypothesize that exercise training during development of obesity will 1) attenuate or prevent obesity-related hypertension, resting tachycardia, neurohumoral activation, and cardiac collagen formation and 2) attenuate obesity-related decreases in responsiveness to Beta-adrenergic stimulation. Abnormalities occurring in sedentary obese rabbits will be compared with their reduction in obese rabbits that undergo 12 weeks of treadmill exercise. Comparisons will also be made with appropriate lean controls. Finally, we will determine mechanisms within the Beta-adrenergic signaling pathway responsible for exercise-mediated increased responsiveness to Beta-adrenergic stimulation in obesity, using appropriate assay and western blotting techniques as noted above. Insight into possible mechanisms whereby obesity causes increased risk for development of congestive heart failure may lead to important advances in therapeutics modalities for prevention and treatment of congestive heart failure in obese patients. Further, information on mechanisms whereby regular endurance exercise may improve cardiovascular risk profile and cardiac performance in obesity may help reduce risk development of cardiovascular disease. Because such a large segment of the American population is overweight or obese, knowledge and insight gained from these studies can have far-reaching effects.

描述（申请人的摘要）：所提议研究的主要目标是确定降低心脏反应性的机制。 肥胖中的β-肾上腺素刺激及其运动训练机制 在肥胖的发展过程中可能会减弱这些影响。我们假设 肥胖会导致血流动力学改变、心脏肥大、心脏 胶原蛋白、荷尔蒙分布和收缩功能独立于 高血压。为了验证这个假设，我们将比较瘦兔子和肥胖兔子 患有高血压和肥胖的兔子，以及肥胖的兔子 使用口服药物将血压控制在肥胖前的值 肼屈嗪。我们将使用心脏的急性和慢性（遥测）测量 速率和血压，以及有色微球，以进行研究 血流动力学。我们将使用蛋白质印迹技术、血液采样、湿法和 干心脏重量和 Langendorff 离体心脏准备进行分析 胶原蛋白、荷尔蒙分布、心脏肥大和收缩功能。我们也 假设降低心脏对β-肾上腺素能的反应 肥胖的刺激是由于心脏和心脏的异常造成的 β 受体和 G 偶联蛋白级联导致 cAMP 形成 以及肌浆网中钙的释放。我们将使用适当的 测定和蛋白质印迹技术提供作用的分析 β-受体和后受体成分，例如β-受体/Gs 偶联， Gs 刺激腺苷酸环化酶； cAMP的形成； PKA的激活，以及 肌浆网钙处理有助于心脏 肥胖异常。我们假设运动训练期间 肥胖的发展将 1) 减轻或预防肥胖相关的 高血压、静息心动过速、神经体液激活和心脏 胶原蛋白的形成和 2) 减轻肥胖相关的反应能力下降 β-肾上腺素能刺激。久坐肥胖发生的异常 兔子将与经过 12 次治疗的肥胖兔子的减少量进行比较 几周的跑步机锻炼。还将与适当的比较 精益控制。最后，我们将确定β-肾上腺素能的机制 负责运动介导的反应性增加的信号通路 使用适当的测定法和蛋白质印迹法刺激肥胖症中的β-肾上腺素能 如上所述的印迹技术。深入了解可能的机制 肥胖导致充血性心力衰竭的风险增加 导致预防和治疗方法的重要进展 治疗肥胖患者的充血性心力衰竭。此外，信息 定期耐力运动可以改善心血管的机制 肥胖的风险状况和心脏功能可能有助于降低心血管疾病的风险发展。因为如此大的一部分 美国人口超重或肥胖，知识和见解来自 这些研究可以产生深远的影响。