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

基本信息

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
项目类别：
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

项目摘要

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.

摘要：主动脉瘤（AA）的特点是主动脉局部异常扩张或膨出。血管壁减弱。 AA发生在主动脉的不同部位，如胸主动脉（TAA）和腹主动脉（AAA）。动脉瘤破裂死亡率很高，需要立即手术修复。主动脉平滑肌细胞（SMC）通过调节主动脉收缩性和弹性，对于减少主动脉壁响应压力至关重要到来自心脏的脉动高压血流。 SMC 丢失和功能障碍可导致内侧退化并有助于 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定调节中发挥关键作用，并且已被被证明是高度特异性的药理干预中有希望的药物靶点。最近，有一些零星的一系列临床和实验证据表明，刺激 cAMP 和 cGMP 信号传导可能具有对 AA 和/或解剖的影响不同，甚至相反。在此应用中，我们将重点关注两个 PDE1 系列同工酶和 AAA。我们实验室和其他人之前的研究表明，在三个 PDE1 成员（1A、 1B 和 1C)，PDE1A 和 1C 是在收缩和/或合成 SMC 中表达的两种主要 PDE1 同工酶。 PDE1A 和 1C 主要分别水解 SMC 中的 cGMP 和 cAMP。我们最近发现，在人类和小鼠主动脉组织中，与正常情况相比，AAA 的合成 SMC 样细胞中 PDE1C 被高度诱导控制。 PDE1A 在正常组织和 AAA 组织的 SMC 中表达。有趣的是，针对 PDE1A 和 1C 可能对 AAA 产生相反的影响：PDE1A 缺乏会加剧，而 PDE1C 缺乏会减弱小鼠实验性 AAA。 PDE1A 调节收缩性 SMC 的收缩性，对于合成非常重要 SMC 存活。然而，PDE1C 诱导会促进 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 的有害作用 SMC 中的抑制作用。这些机制差异可能是造成 AAA 功能差异的原因。因此，我们假设慢性 PDE1C 失活会抑制 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。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 SMC 死亡和 ECM 变性，从而加剧实验诱导的 AAA。一起抑制 PDE1A/1C 可产生针对 AAA 的保护作用，因为 PDE1C 抑制作用超越 PDE1A 抑制的效果。我们将研究PDE1A或1C的调控、功能和机制 AAA 中，并通过靶向 AAA 中的 PDE1 来评估药理作用。此文的翻译意义研究的重点是 PDE1 泛抑制剂已被提议用于临床试验来治疗各种疾病疾病，表明迫切需要研究针对 AA 中 PDE1 同工酶的潜在结果。