Regulation of Cardiac Stress Responses by PDE5a

描述（由申请人提供）：心脏肥厚重塑是心脏病发病率和死亡率的重要组成部分。由于高血压和肥胖的高患病率，它影响了世界上近10%的人口。我们最近发现磷酸二酯酶PDE5a的抑制剂，如西地那非，广泛用于治疗勃起功能障碍的药物，对心功能和应激重塑有强有力的影响。这些和其他支持心脏益处的新数据提高了使用这些药物临床治疗各种心脏病的极大兴趣。然而，人们对它们是如何起作用的知之甚少，特别是在已经存在疾病的相关环境中。在初级水平上，抑制PDE5a可增加环核苷酸cGMP（可直接影响心脏）或活性蛋白激酶G（可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制动器，对基础影响很小，但会减弱儿茶酚胺或病理性应激对心脏的刺激。然而，PDE5a抑制（PDE5a- i）似乎对cGMP水平的改变很小，但却能增强PKG活性，其作用与其他增强cGMP/PKG的方式（如利钠肽刺激）有很大不同。新的数据表明，pde5a抑制作用通过g偶联信号2 （RGS2）和潜在的典型瞬时受体电位（TRPC）通道的调节来抑制激活的G1q通路。这些相互作用的机制，它们如何随着肥厚性疾病的建立而改变，以及为什么慢性pde5a抑制在抑制肥厚的同时改善心功能，这些都是未知的。本提案的研究旨在从三个方面提供这一关键信息，主要是在小鼠模型中进行的研究，使用主动脉带压力过载来刺激肥大/重塑。第一项研究将确定PDE5a-I如何急性改善心功能，以及慢性肥厚性疾病如何改变这种功能。第二点是我们发现PDE5a在翻译后被慢性肥大修饰，改变活性和细胞定位而不是表达，但这影响了它的应激调节。我们要明确这一重点调控机制。最终目的是测试PKG的激活和g1q偶联信号的抑制在压力过载心脏中改善心功能和抗肥厚作用的作用。这些研究的成功完成将极大地扩展我们对PDE5a-I如何调节正常和患病心脏的理解，并为临床试验测试此类药物治疗心脏病提供信息。相关性：世界上近10%的人口心脏肌肉质量增加（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PDE5a酶并广泛用于治疗勃起功能障碍的药物，也可能抑制心脏应激反应。这个项目将确定西地那非是如何起作用的，以及它所涉及的途径，以及它在正常心脏和患病心脏中可能发生的变化。

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.