Monomeric G-proteins and Cardioprotection from Heart Failure

单体G蛋白与心力衰竭的心脏保护作用 美国的心力衰竭发病率正在稳步上升，每年的成本超过300亿美元， 从现在到2030年，成本预计将增加127%。伴随射血分数降低的心力衰竭 (HFrEF)发生在约45%的心衰患者中，与保存完好的心衰患者相比，存活时间更长 射血分数；然而，治疗选择很差，仅限于提高存活率而不能改善 收缩功能。成功的药物，如β阻滞剂，延长寿命(不一定是生活质量) HFrEF转移了人们对HFrEF的基本原则的关注，在HFrEF中，心脏缺陷是不收缩 有足够的力量来满足需求。这一新的建议是由我们对一种新的心脏 Rad-GTP酶缺失引起的表型。Rad缺失小鼠(Rad-/-)显示心肌收缩能力增强 这种情况会持续到衰老，表现优于年龄和性别匹配的动物。Rad-/-老鼠也显示出 防止慢性儿茶酚胺刺激和慢性压力超负荷的心脏保护。在这 我们将测试两类潜在相关但相互排斥的机械论假说。首先，我们 将评估改变的钙稳态对Rad消融的影响；第二，我们将 评估Rad对β-肾上腺素能受体(β-AR)信号轴的贡献。三个互补的目标导向 我们的学习。首先，我们将验证Rad消融通过肌膜增强功能的假设 钙离子内流。这些实验将跨越从分子到整个器官的功能范围。心脏 磁共振成像(CMR)和超声心动图也将用于测量活体心脏功能。 第二，我们将评估Rad缺失通过增强心肌保护作用的假设。 细胞内钙同步性与β-AR信号的保存再说一次，对心脏结构和 功能将跨越从分子到细胞，再到器官水平和体内功能的范围。我们的第三个目标 重点关注Rad缺失作为一种潜在有益的治疗方法。总体而言，这项提议考验了一部小说 增强心脏功能对持续压力提供心脏保护的机制 超负荷和慢性压力信号。

Monomeric G-proteins and Cardioprotection from Heart Failure Heart failure incidence in the United States is steadily increasing with annual costs in excess of $30 billion and the cost is expected to increase 127% between now and 2030. Heart failure with reduced ejection fraction (HFrEF) occurs in ~45% of HF patients and is associated with longer survival compared to HF with preserved ejection fraction; however, treatment options are poor and are limited to increasing survival without improving systolic function. Success of agents, such as β-blockers, to prolong lifespan (not necessarily quality of life) of HFrEF draws attention away from the fundamental principle that in HFrEF the heart defect is failure to contract with sufficient force to meet demand. This new proposal is motivated by our findings of a novel cardiac phenotype caused by deletion of the Rad-GTPase. Rad-null mice (Rad-/-) show increased cardiac contractility that persists well into senescence and out-performs age- and gender-matched animals. Rad-/- mice also show cardioprotection against chronic catecholamine stimulation, and against chronic pressure overload. In this proposal we will test two classes of potentially related but mutually exclusive mechanistic hypothesis. First, we will evaluate the contribution of altered Ca2+ homeostasis in response to Rad ablation; and second, we will assess Rad contributions to the β-adrenergic receptor (β-AR) signaling axis. Three complementary Aims guide our studies. First, we will test the hypothesis that Rad-ablation confers enhanced function via sarcolemmal Ca2+ influx. These experiments will traverse scales of function from molecular to whole organ. Cardiac magnetic resonance imaging (CMR) and echocardiography will also be used to measure in vivo heart function. Second, we will evaluate the hypothesis that Rad deletion contributes to cardioprotection via enhancement of intracellular Ca2+ synchrony and preservation of β-AR signaling. Again, assessments of heart structure and function will traverse scales from molecular, to cellular, to organ level and in vivo function. Our third aim focuses on Rad-deletion as a potentially beneficial therapeutic approach. Overall, this proposal tests a novel mechanism of augmentation of cardiac function that confers cardioprotection against sustained pressure overload and chronic stress signaling.