ALTERED SIGNALING IN CARDIAC HYPERTROPHY AND FAILURE

心脏对慢性压力超负荷的适应导致心脏肥大和信号转导的改变，以补偿增加的交感神经张力和功。 这些适应性变化导致cGMP水平增加，β肾上腺素能受体下调。 这一建议的假设是，cGMP的负面功能效应有助于肥大的补偿，当这种内源性制动失败时，心力衰竭就会发展。 具体目的是确定cGMP的负面影响的机制是通过cGMP依赖性cAMP磷酸二酯酶（PDE）引起的cAMP变化，还是通过蛋白激酶G对A和C的相互作用，为了阐明这些机制中的哪一个导致肥大心脏失代偿，通过对比代偿心脏与衰竭肥大心脏的信号级联的改变，（快速起搏），并通过cAMP PDE的进一步慢性改变证实其相关性。 将使用从具有正常、肥大（主动脉瓣狭窄模型）和衰竭心脏的成年犬中分离的心肌细胞来确定信号传导的后期变化对功能（视频边缘检测）和O2消耗（PO2电极）的影响。 这些机制在控制区域功能和O2消耗方面的相对重要性将在完整心脏中进行测试。 体内实验将在诱导肥大（有或无失败）后6个月在麻醉开胸犬中进行，并与对照组进行比较。 将从节段长度（超声尺寸晶体）和收缩力（微型测力计）评估局部心肌功。 将通过局部血流量（放射性微球或流量探头）和血红蛋白的局部氧饱和度（显微分光光度法）确定相同区域的氧消耗量。 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的生化测定相结合，并与Ca瞬时测量相关联。 最终目标是确定启动失代偿并导致充血性心力衰竭的机制。 提案的影响：对这些机制的理解将允许开发新的治疗策略来预防人的充血性心力衰竭的发展。

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.