Role of cyclic nucleotide signaling in aortic aneurysm

摘要-主动脉瘤(AA)是以局限性异常扩张或膨大为特征的主动脉瘤。 血管壁变弱。AA存在于主动脉的不同部位，如胸主动脉(TAA)和腹主动脉(TAA) (AAA)。动脉瘤破裂死亡率高，需要立即手术修复。主动脉平滑肌 细胞(SMCs)通过调节主动脉的收缩和弹性，对于减少主动脉壁的应激反应是至关重要的。 从心脏流出的脉动高压血流。SMC丢失和功能障碍可导致内侧 退化并促进再生障碍性贫血的发展。CAMP和cGMP是SMC收缩的重要调节因子 功能和管壁结构的完整性。环核苷酸磷酸二酯酶(PDE)，催化cAMP 和/或cGMP降解，在环核苷酸信号的特异性调控中发挥关键作用，并已被 在高度特异的药理干预中被证明是很有希望的药物靶点。最近，一些零星的 一系列临床和实验证据表明，刺激cAMP和cGMP信号可能具有 对再生障碍性贫血和/或夹层的影响不同，甚至相反。在本申请中，我们将重点介绍两个PDE1系列 同工酶和AAA。我们实验室和其他实验室之前的研究表明，在三个PDE1成员(1A， 1B和1C)、PDE1A和1C是在收缩和/或合成的SMC中表达的两种主要的PDE1同工酶。 PDE1A和1C在SMC中分别主要降解cGMP和cAMP。我们最近发现，在人类 和小鼠主动脉组织，与正常相比，PDE1C在合成的AAA SMC样细胞中被高度诱导 控制。PDE1a在正常和AAA组织的SMC中均有表达。有趣的是，目标是PDE1A和1C 在AAA中可能有相反的影响：PDE1A缺乏加剧，而PDE1C缺乏减弱 小鼠实验性AAA。PDE1a调节收缩的SMC的收缩性能，并且对合成 SMC生存。然而，PDE1C诱导可促进SMC表型转换、衰老和死亡。 有趣的是，PDE1C抑制的保护作用克服了PDE1A的有害影响 SMC的抑制作用。这些机制上的差异可能是它们在AAA中功能差异的原因。 因此，我们假设慢性PDE1C失活抑制SMC表型转换、衰老、 死亡和细胞外基质变性(如MMPs)，从而减弱实验诱导的小鼠AAA。相比之下， 慢性PDE1A失活会导致SMC收缩功能障碍，增加主动脉壁压力，以及 促进合成的SMC死亡和ECM退化，从而加剧实验诱导的AAA。 同时抑制PDE1A/1C可产生对AAA的保护作用，因为PDE1C抑制的作用 覆盖PDE1A抑制的效果。我们将研究PDE1A或1C的调节、功能和机制 并以PDE1为靶点评价其对AAA的药理作用。这句话的翻译意义 研究的重点是PDE1PAN抑制剂已被提议用于临床试验，以治疗各种 疾病，表明迫切需要研究靶向PDE1同工酶在再生障碍性贫血中的潜在结果。

ABSTRACT- Aortic aneurysm (AA) is characterized by localized abnormal dilatation or bulging of aorta due to weakened vessel wall. AA occurs in different sections of aorta, such as thoracic AA (TAA) and abdominal AA (AAA). The rupture of aneurysm has high mortality and requires immediate surgical repair. Aortic smooth muscle cells (SMCs), by regulating aortic contractility and elasticity, are critical for reducing aortic wall stress in response to the pulsatile high-pressure blood flow from the heart. SMC loss and dysfunction can cause medial degeneration and contribute to AA development. cAMP and cGMP, are important regulators of SMC contractile function and vessel wall structural integrity. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing cAMP and/or cGMP degradation, play crucial roles in specific modulation of cyclic nucleotide signaling and have been proved to be promising drug targets in highly specific pharmacological interventions. Recently, a few sporadic lines of clinical and experimental evidence have suggested that stimulating cAMP and cGMP signaling may have different, even opposite, effects on AA and/or dissection. In this application, we will focus on two PDE1 family isozymes and AAA. Previous studies from our lab and others have shown that among three PDE1 members (1A, 1B, and 1C), PDE1A and 1C are two major PDE1 isozymes expressed in contractile and/or synthetic SMCs. PDE1A and 1C primarily hydrolyze cGMP and cAMP, respectively, in SMCs. We recently found that in the human and mouse aortic tissues, PDE1C is highly induced in synthetic SMC-like cells of AAA compared to normal controls. PDE1A is expressed in SMCs of both normal and AAA tissues. Interestingly, targeting PDE1A and 1C likely have opposing effects in AAA: PDE1A deficiency aggravates while PDE1C deficiency attenuates experimental AAA in mice. PDE1A regulates the contractility of contractile SMCs, and is important for synthetic SMC survival. However, PDE1C induction promotes SMC phenotype switching, senescence, and death. Interestingly, the protective effects from PDE1C inhibition overcome the detrimental effects from PDE1A inhibition in SMCs. These mechanistic differences may be responsible for their functional differences in AAA. Thus, we hypothesize that chronic PDE1C inactivation suppresses SMC phenotype switching, senescence, death, and ECM degeneration (e.g. MMPs), thus attenuating experimentally induced mouse AAA. In contrast, chronic PDE1A inactivation causes SMC contractile dysfunction and increases aortic wall stress, as well as promotes synthetic SMC death and ECM degeneration, thus exacerbating experimentally induced AAA. Inhibiting PDE1A/1C together produces a protective effect against AAA because the effect of PDE1C inhibition overrides the effect of PDE1A inhibition. We will study the regulation, function and mechanism of PDE1A or 1C in AAA and evaluate the pharmacological effects by targeting PDE1 in AAA. The translational significance of this study is highlighted by the fact that PDE1 pan inhibitors have been proposed for clinical trials to treat various diseases, suggesting an urgent need to investigate the potential outcomes of targeting PDE1 isozymes in AA.