Impact of PDE2 modulation in Heart Failure and Arrhythmia

PDE2 调节对心力衰竭和心律失常的影响

• 批准号: 289281296
• 负责人: Professor Dr. Ali El-Armouche
• 金额: --
• 依托单位: Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/289281296?language=en
• 关键词: Impact; PDE2; modulation; Heart; Failure

Heart failure and lethal ventricular arrhythmias remain one of the leading causes of mortality worldwide and innovative therapeutic concepts are highly desired. While traditional therapies inhibit the deleterious activation of neurohormonal systems (such as the β-adrenergic pathway and the renin-angiotensin-aldosterone system), novel concepts also aim at activating protective pathways, e.g. additional augmentation of the natriuretic peptide (NP) system. Phosphodiesterase 2 (PDE2) is a signalling node, connecting the β-adrenergic and NP systems. Among the PDEs, it has the unique property to be stimulated by cGMP leading to increased cAMP hydrolysis and thus mediating a negative cross-talk between cAMP/cGMP pathways. While the pathophysiological role of PDE2 in the heart is in a large part unknown and still being controversially discussed, our data point to a cardioprotective and antiarrhythmic role of PDE2 as well as of PDE2-mediated cGMP/cAMP crosstalk in heart disease. Our goal is to define the physiological and pathophysiological role of PDE2 in the heart. To this aim, we will capitalize from newly developed cardiac-specific PDE2 knockout models. We will combine in vivo and in vitro techniques to decipher the impact of PDE2 on cardiac function as well as its functions in subcellular cGMP/cAMP crosstalk. We will validate our main findings in an inducible cardiac-specific PDE2 knockout model. Moreover, we will provide mechanistic insights into cardiac subcellular cAMP-regulation by the three PDE2 isoforms under physiological conditions, into the antiarrhythmic effects of PDE2 at animal, organ and cellular level and into PDE2 functions during cardiac remodeling in established heart failure models. Finally, we will provide proof-of-concept of therapeutic PDE2 stimulation by pharmacological treatment of wild type and PDE2 KO mice with cGMP-enhancing NO-donors as well as NPs. Unravelling the mechanistic role of PDE2 in heart failure and arrhythmias may serve to develop innovative new therapeutic approaches by pharmacologically modulating PDE2 activity.

心力衰竭和致死性室性心律失常仍然是世界范围内死亡的主要原因之一，创新的治疗理念是高度需要的。虽然传统疗法抑制神经激素系统（如β-肾上腺素能通路和肾素-血管紧张素-醛固酮系统）的有害激活，但新概念也旨在激活保护性通路，例如额外增强利钠肽（NP）系统。磷酸二酯酶2 （PDE2）是连接β-肾上腺素能和NP系统的信号节点。在pde中，它具有独特的特性，可以受到cGMP的刺激，导致cAMP水解增加，从而介导cAMP/cGMP通路之间的负串扰。虽然PDE2在心脏中的病理生理作用在很大程度上是未知的，并且仍在有争议的讨论中，但我们的数据表明PDE2以及PDE2介导的cGMP/cAMP串扰在心脏病中的心脏保护和抗心律失常作用。我们的目标是确定PDE2在心脏中的生理和病理生理作用。为此，我们将利用新开发的心脏特异性PDE2敲除模型。我们将结合体内和体外技术来破译PDE2对心脏功能的影响及其在亚细胞cGMP/cAMP串扰中的功能。我们将在一个可诱导的心脏特异性PDE2敲除模型中验证我们的主要发现。此外，我们将提供生理条件下三种PDE2亚型对心脏亚细胞camp调节的机制，在动物、器官和细胞水平上PDE2的抗心律失常作用，以及在已建立的心力衰竭模型中PDE2在心脏重塑过程中的功能。最后，我们将通过药物治疗野生型和PDE2 KO小鼠cgmp增强no供体以及NPs，提供治疗性PDE2刺激的概念证明。揭示PDE2在心力衰竭和心律失常中的机制作用可能有助于通过药理学调节PDE2活性来开发创新的新治疗方法。