Regulation of Cardiac Stress Responses by PDE5a

描述（由申请人提供）：心脏肥大性重塑是心脏病发病率和死亡率的重要组成部分。 由于高血压和肥大的高患病率，它影响了世界上近10%的人口。我们最近发现磷酸二酯酶PDE 5a的抑制剂，如西地那非，广泛用于治疗勃起功能障碍的药物，对心脏功能和压力重塑有强大的影响。 这些和其他支持心脏益处的新数据引起了人们对使用这些药物临床治疗心脏病形式的极大兴趣。 然而，关于它们是如何工作的，特别是在已经建立疾病的相关环境中，人们知之甚少。在初级水平，抑制PDE 5a增加环核苷酸cGMP，这可以直接影响心脏，或活性蛋白激酶G，然后影响多种蛋白质以改变应激反应。cGMP/PKG系统的功能很像一个刹车，几乎没有基础的影响，但钝心刺激的儿茶酚胺或病理应激。 然而，PDE 5a抑制（PDE 5a-I）似乎几乎不改变cGMP水平，同时增强PKG活性，并且具有与增强cGMP/PKG的其他方式（如利钠肽刺激）完全不同的效果。 新的数据表明，PDE 5a抑制通过G偶联信号2（RGS 2）和潜在的经典瞬时受体电位（TRPC）通道的调节剂在抑制激活的G1 q通路中发挥着重要作用。这些相互作用的机制，它们如何随着肥大性疾病的建立而变化，以及为什么慢性PDE 5a抑制在抑制肥大的同时改善心脏功能尚不清楚。 本提案中的研究旨在提供三个目标的关键信息，主要在小鼠模型中进行研究，使用动脉结扎带压力超负荷刺激肥大/重塑。 第一个将确定PDE 5a-I如何急性改善心脏功能以及慢性肥厚性疾病如何改变心脏功能。第二个是我们的发现，即PDE 5a被慢性肥大后修饰，改变活性和细胞定位低于表达，但这影响了其应激调节。我们将确定这一关键监管的机制。 最终目的是测试PKG激活和抑制G1 q偶联信号传导在压力超负荷心脏中改善心脏功能和抗肥大作用的作用。 这些研究的成功完成将极大地扩展我们对PDE 5a-I如何调节正常和患病心脏的理解，并为测试此类药物治疗心脏病的临床试验提供信息。释放：世界上近10%的人口发展为心脏肌肉质量增加（肥大），这增加了他们患心脏病的风险。 我们发现，西地那非（伟哥），一种阻断酶PDE 5a的药物，被广泛用于治疗勃起功能障碍，也可能抑制心脏应激反应。 该项目将确定西地那非是如何工作的，以及所涉及的途径，以及这可能如何在正常情况下改变，而不是患病的心脏。

DESCRIPTION (provided by applicant): Cardiac hypertrophic remodeling underlies a large component of the morbidity and mortality of heart disease. It affects nearly 10% of the world's population given the high prevalence of hypertension and hypertrophy that evolves with it. We recently discovered that inhibitors of the phosphodiesterase PDE5a such as sildenafil, drugs widely used to treat erectile dysfunction, have potent effects on cardiac function and stress-remodeling. These and other new data supporting cardiac benefits have raised substantial interest for using these drugs to clinically treat forms of heart disease. However, remarkably little is known about how they are working particularly in the relevant setting where there disease is already established. At the primary level, inhibiting PDE5a increases the cyclic nucleotide cGMP, that can influence the heart directly, or active protein kinase G which then influences multiple proteins to modify the stress response. The cGMP/PKG system functions much like a brake, having little basal impact, but blunting cardiac stimulation by catecholamines or pathologic stress. Yet, PDE5a inhibition (PDE5a-I) appears to change cGMP levels little, while enhancing PKG activity and has effects that are quite different from other ways of enhancing cGMP/PKG (such as natriuretic peptide stimulation). New data suggests a prominent role of PDE5a-inhibition in suppressing activated G1q pathways via regulator of G-coupled signaling 2 (RGS2) and potentially canonical transient receptor potential (TRPC) channels. The mechanisms for these interactions, how they change as hypertrophic disease becomes established, and why chronic PDE5a-inhibition improves cardiac function while suppressing hypertrophy are unknown. The research in this proposal aims to provide this critical information in three aims, with studies conducted largely in mouse models, using aortic-banding pressure-overload to stimulate hypertrophy/remodeling. The first will determine how PDE5a-I acutely improves cardiac function and how this is altered by chronic hypertrophic disease. The second hones in our finding that PDE5a is post- translationally modified with chronic hypertrophy, altering activity and cellular localization less than expression, but that this impacts its stress modulation. We will identify mechanisms for this key regulation. The final aim tests the role of PKG activation and suppression of G1q-coupled signaling for both improved cardiac function and anti-hypertrophic effects in pressure-overloaded hearts. The successful completion of these studies will greatly expand our understanding of how PDE5a-I modulates normal and diseased hearts, and inform clinical trials testing such drugs for treating heart disease. RELEVENCE: Nearly 10% of the world's population develops an increase in muscle mass (hypertrophy) of their heart which increases their risk of suffering from heart disease. We discovered that sildenafil (Viagra), a drug that blocks the enzyme PDE5a and is widely used to treat erectile dysfunction, may also suppress cardiac stress-responses. This project will determine how sildenafil is working and the pathways that are involved, and how this may change in normal as opposed to diseased hearts.