Role of cyclic nucleotide signaling in aortic aneurysm

环核苷酸信号传导在主动脉瘤中的作用

• 批准号: 10634733
• 负责人: Chen Yan
• 金额: $ 55.34万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634733
• 关键词: Abdominal Aortic Aneurysm; Ablation; Aging; Aneurysm; Aorta; Aortic Aneurysm; Apoptosis; Attenuated; Binding Sites; Blood Vessels; Blood flow; Cause of Death; Cell Death; Cell Survival; Cells; Cessation of life; Chronic; Clinical; Clinical Treatment; Clinical Trials; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotides; Data; Data Analyses; Development; Dilatation - action; Disease; Dissection; Drug Targeting; Elasticity; Enzymes; Extracellular Matrix; Family; Functional disorder; Genes; Grant; Heart; Heart failure; Human; Hypertension; In Vitro; Intervention; Isoenzymes; Knock-out; Knockout Mice; Life; Link; Matrix Metalloproteinases; Medial; Metadata; Modeling; Mus; Nucleic Acid Regulatory Sequences; Operative Surgical Procedures; Outcome; Pathogenesis; Pathogenicity; Patients; Phenotype; Play; Population; Preparation; Production; Protein Kinase; Public Health; Publishing; Regulation; Role; Rupture; Ruptured Aneurysm; Ruptured Aortic Aneurysms; Schizophrenia; Signal Transduction; Site; Smooth Muscle Myocytes; Stress; Thoracic Aortic Aneurysm; Tissues; forkhead protein; gain of function mutation; in vivo; inhibitor; member; mortality; mouse model; novel; pharmacologic; phosphoric diester hydrolase; prevent; protective effect; repaired; response; senescence; single-cell RNA sequencing; transcriptome

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.

抽象性主动脉瘤（AA）的特征是由于局部异常扩张或主动脉膨胀 减弱的容器壁。 AA发生在主动脉的不同部分，例如胸AA（TAA）和腹部AA （AAA）。动脉瘤的破裂具有高死亡率，需要立即进行手术修复。主动脉平滑肌 通过调节主动脉收缩性和弹性来调节细胞（SMC），对于减少主动脉壁应力至关重要 从心脏的脉动高压血流。 SMC损失和功能障碍可能导致内侧 退化并为AA发展做出贡献。 CAMP和CGMP是SMC收缩的重要监管机构 功能和容器壁结构完整性。循环核苷酸磷酸二酯酶（PDES），通过催化营 和/或CGMP降解，在环状核苷酸信号的特定调制中起着至关重要的作用，并且已经是 在高度特定的药理干预措施中被证明是有希望的药物靶标。最近，一些零星 临床和实验证据的线表明，刺激营地和CGMP信号可能具有 对AA和/或解剖的影响，甚至相反。在此应用程序中，我们将重点关注两个PDE1家族 同工酶和AAA。我们实验室和其他人的先前研究表明，在三个PDE1成员中（1a， 1B和1C），PDE1A和1C是在收缩和/或合成SMC中表达的两个主要PDE1。 PDE1A和1C主要在SMC中分别水解CGMP和CAMP。我们最近发现在人类中 小鼠主动脉组织，PDE1C在AAA的合成SMC样细胞中高度诱导 控件。 PDE1a在正常组织和AAA组织的SMC中表达。有趣的是，针对PDE1A和1C 在AAA中可能产生相反的影响：PDE1A缺陷会加剧，而PDE1C缺乏症会减弱 小鼠实验AAA。 PDE1A调节收缩SMC的收缩性，对合成很重要 SMC生存。但是，PDE1C诱导促进了SMC表型切换，衰老和死亡。 有趣的是，PDE1C抑制的保护作用克服了PDE1A的不利影响 SMC的抑制作用。这些机械差异可能是其在AAA中的功能差异的原因。 因此，我们假设慢性PDE1C失活抑制了SMC表型转换，衰老， 死亡和ECM变性（例如MMP），从而减弱了实验诱导的小鼠AAA。相比之下， 慢性PDE1A失活会导致SMC收缩功能障碍，并增加主动脉壁应力以及 促进合成的SMC死亡和ECM变性，从而加剧了实验诱导的AAA。 抑制PDE1A/1C共同对AAA产生保护作用，因为PDE1C抑制作用 覆盖PDE1A抑制作用。我们将研究PDE1A或1C的调节，功能和机制 在AAA中，并通过靶向AAA中的PDE1来评估药理作用。翻译意义的意义 PDE1 PAN抑制剂已提出用于治疗各种的PDE1 PAN抑制剂以下事实强调了研究 疾病，表明迫切需要研究靶向AA中PDE1的潜在结果。