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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：
10538778
负责人：
Chen Yan
金额：
$ 58.04万
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/10538778
关键词：
Abdomen 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 Chest 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 Pharmacology 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 base forkhead protein gain of function mutation in vivo inhibitor member mortality mouse model novel 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（Aortic动脉瘤，AA）是一种以动脉局部异常扩张或膨出为特征的疾病