ALTERED SIGNALING IN CARDIAC HYPERTROPHY AND FAILURE

心脏肥大和心力衰竭的信号改变

• 批准号: 6389059
• 负责人: PETER M SCHOLZ
• 金额: $ 47.48万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389059
• 关键词: 3'5' cyclic nucleotide phosphodiesterase; adenylate cyclase; aortic valve stenosis; biological signal transduction; calcium flux; cardiac myocytes; congestive heart failure; cyclic AMP; cyclic GMP; disease /disorder model; dogs; enzyme activity; guanylate cyclase; heart circulation; heart contraction; heart function; molecular pathology; oximetry; oxygen consumption; phosphorylation; protein kinase; protein kinase A; protein kinase C; tissue /cell culture; ventricular hypertrophy

Adaptation of the heart to chronic pressure overload leads to cardiac hypertrophy and alterations in signal transduction to compensate for increased sympathetic tone and work. These adaptive changes lead to increases in cGMP levels down regulation of beta adrenergic receptors. The hypothesis of this proposal is that the negative functional effects of cGMP contribute to compensation in hypertrophy and that, when this endogenous brake fails, heart failure develops. The specific aim is to determine if the mechanism of cGMP's negative impact is through changes in cAMP via the cGMP-dependent cAMP phosphodiesterases (PDE) or through interactions of protein kinase G on A and C, to elucidate which of these mechanisms causes the hypertrophied heart to decompensate by contrasting the alterations in the signaling cascade of the compensated with that of failing hypertrophied heart (rapid pacing) and to confirm their relevance by further chronic alteration of the cAMP PDEs. Cardiac myocytes isolated from adult dogs with normal, hypertrophied (aortic stenosis model) and failing hearts will be used to determine the effects of postproduction changes in signaling on function (video edge detection) and O2 consumption (PO2 electrode). The relative importance of these mechanisms in controlling regional function and O2 costs will be tested in the intact heart. The in vivo experiments will be conducted in anesthetized, open-chest dogs 6 months after induction of hypertrophy with or without failure and compared to controls. Regional myocardial work will be assessed from segment length (ultrasonic dimension crystals) and contractile force (miniature force gauges). O2 consumption of the same area will be determined from regional blood flow (radioactive microspheres or flow probe) and regional O2 saturation of hemoglobin (microspectrophotometry). These physiological measurements will be combined with biochemical assays for cAMP, cGMP, the respective phosphodiesterases and protein kinases A, G and C and correlated with Ca transient measurements. The ultimate goal is to determine the mechanism that initiates decompensation and leads to congestive heart failure. Impact of the proposal: the understanding of these mechanisms will permit the development of new therapeutic strategies to prevent the development of congestive heart failure in man.

心脏对慢性压力超负荷的适应会导致心脏肥大和信号转导的改变，以补偿增加的交感神经音调和工作。 这些适应性变化导致CGMP水平升高降低β肾上腺素能受体的调节。 该提议的假设是，CGMP的负功能效应有助于肥大的补偿，并且当该内源制动失败时，心力衰竭就会发展。 The specific aim is to determine if the mechanism of cGMP's negative impact is through changes in cAMP via the cGMP-dependent cAMP phosphodiesterases (PDE) or through interactions of protein kinase G on A and C, to elucidate which of these mechanisms causes the hypertrophied heart to decompensate by contrasting the alterations in the signaling cascade of the compensated with that of failing hypertrophied heart (rapid pacing) and to通过进一步改变营地PDES来确认它们的相关性。 从具有正常，肥大的（主动脉狭窄模型）和心脏失败的成年犬中分离出的心肌细胞将用于确定信号传导对功能（视频边缘检测）和O2消耗（PO2电极）的影响的影响。 这些机制在控制区域功能和O2成本中的相对重要性将在完整的心脏中进行测试。 体内实验将在诱导肥大后6个月内在麻醉的开放式狗中进行，并与对照组相比。 区域心肌工作将从段长度（超声尺寸晶体）和收缩力（微型力量计）评估。 O2的消耗将由区域血流（放射性微球或流量探针）和血红蛋白（微光照射测定法）的区域O2饱和度确定。 这些生理测量将与CAMP，CGMP，相应的磷酸二酯酶和蛋白激酶A，G和C的生化测定法相结合，并与CA瞬时测量相关。 最终目标是确定启动代偿作用的机制并导致充血性心力衰竭。 提案的影响：对这些机制的理解将允许制定新的治疗策略，以防止人类的充血性心力衰竭发展。