Role of cyclic nucleotide signaling in aortic aneurysm

摘要-主动脉瘤（AA）的特征是局部异常扩张或主动脉膨出， 削弱血管壁。AA发生在主动脉的不同节段，如胸AA（TAA）和腹AA （AAA）。动脉瘤破裂死亡率高，需要立即手术修复。主动脉平滑肌 平滑肌细胞（SMCs）通过调节主动脉收缩性和弹性，对于降低主动脉壁应力是至关重要的 心脏的脉动高压血流。SMC损失和功能障碍可导致 退化，并有助于AA的发展。cAMP和cGMP是SMC收缩的重要调节因子， 功能和血管壁结构完整性。环核苷酸磷酸二酯酶（PDE），通过催化cAMP 和/或cGMP降解，在环核苷酸信号传导的特异性调节中起关键作用， 在高度特异性的药理学干预中被证明是有前途的药物靶点。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AA和/或夹层的不同甚至相反的影响。在本申请中，我们将重点关注两个PDE 1家族 同工酶和AAA。我们实验室和其他人以前的研究表明，在三个PDE 1成员（1A， PDE 1A和1C是在收缩和/或合成SMC中表达的两种主要的PDE 1同工酶。 PDE 1A和1C分别主要水解SMC中的cGMP和cAMP。我们最近发现， 和小鼠主动脉组织中，PDE 1C在AAA的合成SMC样细胞中的诱导程度高于正常细胞 对照PDE 1A在正常和AAA组织的SMC中表达。有趣的是，靶向PDE 1A和1C 在AAA中可能有相反的作用：PDE 1A缺乏会加重，而PDE 1C缺乏会减弱 小鼠实验性AAA。PDE 1A调节收缩性SMC的收缩性，并且对于合成 SMC存活率。然而，PDE 1C诱导促进SMC表型转换、衰老和死亡。 有趣的是，PDE 1C抑制的保护作用克服了PDE 1A的有害作用 SMC中的抑制。这些机制的差异可能是负责在AAA中的功能差异。 因此，我们假设慢性PDE 1C失活抑制SMC表型转换、衰老， 死亡和ECM变性（例如MMP），从而减弱实验诱导的小鼠AAA。与此相反的是， 慢性PDE 1A失活导致SMC收缩功能障碍并增加主动脉壁应力，以及 促进合成SMC死亡和ECM变性，从而加剧实验诱导的AAA。 抑制PDE 1A/1C一起产生对AAA的保护作用，因为PDE 1C抑制的作用 抑制PDE 1A的效果。我们将研究PDE 1A或1C的调控、功能和作用机制 并通过靶向PDE 1在AAA中的药理作用进行评价。这个翻译的意义 一项研究强调了这样一个事实，即PDE 1泛抑制剂已被提议用于临床试验，以治疗各种疾病。 疾病，这表明迫切需要研究在AA中靶向PDE 1同工酶的潜在结果。

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.