Regulation of Cardiac Stress Responses by PDE5a

心脏肥厚重塑是心源性心脏病发病率和死亡率的重要组成部分。 心脏病。鉴于高血压的高患病率，它影响着世界上近10%的人口 以及随之而来的肥大。我们最近发现，磷酸二酯酶的抑制剂 PDE5a，如西地那非，广泛用于治疗勃起功能障碍的药物，对心脏有强大的作用。 功能和应力重塑。这些和其他支持心脏益处的新数据提高了 对使用这些药物在临床上治疗各种形式的心脏病非常感兴趣。然而，值得注意的是， 人们对它们是如何工作的知之甚少，特别是在有疾病的相关环境中 已经建立了。在初级水平上，抑制PDE5a会增加环核苷酸cGMP，即 可以直接影响心脏，或活性蛋白激酶G，进而影响多个蛋白质 修改压力响应。CGMP/PKG系统的功能很像刹车，几乎没有基础 对儿茶酚胺或病理性应激的影响，但钝化心脏刺激。然而，PDE5a抑制 (PDE5a-I)似乎几乎不改变cGMP水平，而增强PKG活性，并具有 与其他增强cGMP/PKG的方法(如利钠肽刺激)有很大不同。新的 数据表明，PDE5a抑制在通过调节抑制激活的G？Q通路中具有显著作用 G偶联信号转导2(RGS2)和潜在的典型瞬时受体电位(TRPC)通道。 这些相互作用的机制，以及它们如何随着肥厚性疾病的建立而变化， 为什么长期抑制PDE5a可以改善心脏功能，同时抑制肥厚 未知。这项建议中的研究旨在通过三个目标提供这一关键信息，包括 研究主要在小鼠模型中进行，使用主动脉环扎压力超负荷来刺激 肥大/重构。第一项将确定PDE5a-I如何显著改善心功能和 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POST 翻译修饰为慢性肥大，改变活动和细胞定位少于 表达，但这影响了它的应力调节。我们将确定此密钥的机制 监管。最终目的是测试PKG激活和抑制G？Q偶联信号在 在压力超负荷的心脏中，既能改善心功能，又能抗肥厚。这个 这些研究的成功完成将极大地扩展我们对PDE5a-I如何调节的理解 正常和患病的心脏，并为测试此类药物治疗心脏病的临床试验提供信息。世界上近10%的人口患上了肌肉肥大 他们的心脏，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。这个项目将决定如何 西地那非的作用和涉及的途径，以及在正常的AS中这种情况可能会如何改变 反对病态的心脏。

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 G?q 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 G?q-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. 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.