Regulation of Cardiac Stress Responses by PDE5a

描述(由申请人提供)：心脏肥厚重构是心脏病发病率和死亡率的重要组成部分。鉴于随之而来的高血压和肥厚的高患病率，它影响着世界上近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，对心脏功能和应激重塑有强大的影响。这些和其他支持心脏益处的新数据已经引起了人们对使用这些药物临床治疗各种形式的心脏病的浓厚兴趣。然而，令人惊讶的是，人们对它们是如何工作的知之甚少，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会增加环核苷酸cGMP，这可以直接影响心脏，或者增加活性蛋白激酶G，然后影响多个蛋白质来改变应激反应。CGMP/PKG系统的功能类似于刹车，对基础影响很小，但可以钝化儿茶酚胺或病理应激对心脏的刺激。然而，PDE5a抑制(PDE5a-I)似乎对cGMP水平变化不大，但却增强了PKG活性，并且具有与其他增强cGMP/PKG的方法(如利钠肽刺激)截然不同的效果。新的数据表明，PDE5a抑制通过调节G偶联信号2(RGS2)和潜在的典型瞬时受体潜力(TRPC)通道，在抑制激活的G1q通路中起着显著的作用。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尚不清楚。这项建议中的研究旨在通过三个目标提供这一关键信息，主要是在小鼠模型上进行研究，使用主动脉环扎压力超负荷来刺激肥大/重构。第一个将确定PDE5a-I如何显著改善心脏功能，以及慢性肥厚性疾病如何改变这一点。第二个问题是我们发现PDE5a是翻译后修饰的，具有慢性肥大，改变活性和细胞定位，而不是表达，但这影响了它的应力调节。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G1q偶联信号对于改善压力超负荷心脏的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，并为测试这种药物治疗心脏病的临床试验提供信息。背景：世界上近10%的人口心脏肌肉质量增加(肥大)，这增加了他们罹患心脏病的风险。我们发现，西地那非(伟哥)，一种阻断PDE5a酶的药物，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起作用的，涉及的途径，以及这种情况在正常心脏和疾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.