The Role of Amino Acid Starvation Response Kinase GCN2 in Abdominal Aortic Aneurysm

氨基酸饥饿反应激酶 GCN2 在腹主动脉瘤中的作用

• 批准号: 10584543
• 负责人: Bowen Wang
• 金额: $ 40.99万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584543
• 关键词: Abdominal Aortic Aneurysm; Adopted; American; Amino Acids; Angiotensin II; Aorta; Arginine; Arginine deiminase; Automobile Driving; Biological; Biological Assay; Caloric Restriction; Cardiovascular Diseases; Cell Survival; Cells; Clinical; Clinical Management; Co-Immunoprecipitations; Cytoprotection; Development; Diameter; Dietary Intervention; Disease; Elastases; Elderly; Exhibits; Functional disorder; Gender; Genetic Transcription; Health; Health Benefit; Homeostasis; Human; In Vitro; Inflammatory; Intervention; Intervention Studies; Knock-out; Knockout Mice; Lead; Lesion; Leucine; Life; Mediating; Medical; Metabolic stress; Methionine; Modeling; Molecular; Mus; Mutation; Newly Diagnosed; Operative Surgical Procedures; Outcome; Paracrine Communication; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phosphotransferases; Pilot Projects; Play; Population; Post-Translational Protein Processing; Prevention; Proteins; Rattus; Recombinant Proteins; Regulation; Repression; Resistance; Risk Reduction; Rodent; Role; Rupture; Signal Transduction; Smooth Muscle Myocytes; Specimen; Starvation; Testing; Therapeutic; Time; Transgenic Organisms; Vascular Smooth Muscle; abdominal aorta; activating transcription factor 3; combat; cost; dietary; dietary restriction; effective intervention; effective therapy; gain of function; in vivo; innovation; knock-down; loss of function; mortality; multi-ethnic; mutant; novel; prevent; repaired; response; screening; stress kinase; success; transcription factor

Project Summary: Abdominal aortic aneurysm (AAA) is a life-threatening disease that afflicts ~1.5 million Americans, particularly in the elderly populations. Despite its high mortality (80-90%) upon rupture, there is a lack of effective drug therapies for clinical management of AAA. Surgical repairs remain the only effective options; however, not only are they considered traumatic and risky, but also not indicated for the majority of newly diagnosed AAA patients. Therefore, there is a pressing unmet need to develop non-surgical strategies to contain AAA progression. Dietary restrictions of amino acids emerge as promising avenues to combat cardiovascular diseases. For the first time, our study demonstrated the potential of dietary methionine or leucine restrictions in inhibiting the development of AAA in a rat model. It is well established that such dietary restrictions trigger the amino acid starvation response, a potent protective mechanism driven by the metabolic stress kinase general control nondepressible 2 (GCN2). Indeed, in our preliminary study, silencing GCN2 in rat abdominal aorta nullified the benefits of methionine restriction against AAA, suggesting a protective role of GCN2 in reinstating aortic homeostasis. Activating GCN2 through methionine restriction protected smooth muscle cells (SMCs) from undergoing degeneration, which is one of the key determinants of AAA pathogenesis; conversely, reduced GCN2 activity was robustly observed in clinical specimens of AAA, and GCN2 silencing effectively compromised the protection against SMC degeneration. Finally, we serendipitously identified GCN2 to be citrullinated by peptidyl arginine deiminase 3 (PADI3) at its 1475 arginine (R1475) residue in the starvation-sensing domain. This post-translational modification (PTM) of GCN2 was increased in AAA and correlated with repressed GCN2 activity. Collectively, these preliminary results lead to our central hypothesis: GCN2 plays a pivotal role in protecting against SMC degeneration and AAA formation, and its activity is negatively modulated by PADI3-mediated citrullination; GCN2-activating strategies offer a new paradigm for effective prevention and intervention of AAA. In Aim 1, we will dissect the role of GCN2 in safeguarding SMC homeostasis as well as its downstream signaling using human and murine SMCs. In Aim 2, we will characterize a new PTM regulation that negatively modulates GCN2 activity and delineate the biological consequences of GCN2 citrullination in SMC. In Aim 3, we will determine the mechanistic and therapeutic implications of GCN2 activation in AAA, utilizing both transgenic (SMC-specific GCN2 knockout mice) and dietary intervention approaches (methionine restriction for treatment of pre-existing AAA lesions). The successful completion of the proposed studies will not only uncover an intrinsic protective mechanism against SMC degeneration and AAA pathogenesis, but also may provide a new paradigm through GCN2-activating dietary restrictions for effective prevention and intervention of AAA.

腹主动脉瘤（AAA）是一种危及生命的疾病，约有150万人患有这种疾病。 美国人，尤其是老年人。尽管其破裂后的死亡率高（80-90%），但 缺乏有效的药物治疗AAA的临床管理。手术修复仍然是唯一有效的 选择;然而，它们不仅被认为是创伤性的和有风险的，而且也不适用于大多数人。 新诊断的AAA患者。因此，迫切需要开发非手术策略， 包含AAA进展。限制氨基酸的饮食是一种有希望的对抗 心血管疾病我们的研究第一次证明了膳食蛋氨酸或 亮氨酸限制抑制大鼠模型中AAA的发展。众所周知，这种饮食 限制引发氨基酸饥饿反应，这是一种由代谢驱动的有效保护机制。 应激激酶一般控制不可抑制蛋白2（GCN 2）。事实上，在我们的初步研究中，沉默大鼠GCN 2 腹主动脉取消了蛋氨酸限制对AAA的益处，这表明 GCN 2在恢复主动脉稳态中的作用。通过蛋氨酸限制性酶切激活GCN 2， 肌肉细胞（SMC）发生变性，这是AAA的关键决定因素之一 发病机制;相反，在AAA的临床标本中强烈观察到GCN 2活性降低， GCN 2沉默有效地损害了对SMC变性的保护。最后，我们偶然地 经鉴定，GCN 2在其1475精氨酸（R1475）处被肽基精氨酸脱亚胺酶3（PADI 3）瓜氨酸化 饥饿感应域中的残基。GCN 2的这种翻译后修饰（PTM）增加， AAA与抑制的GCN 2活性相关。总的来说，这些初步结果导致我们的中央 假设：GCN 2在防止SMC变性和AAA形成中起关键作用， 活性受到PADI 3介导的瓜氨酸酶的负调节; GCN 2激活策略提供了一种新的 有效预防和干预AAA的范例。在目标1中，我们将剖析GCN 2在以下方面的作用： 使用人和鼠SMC保护SMC稳态及其下游信号传导。在目标2中， 我们将描述一个新的PTM调节，负调节GCN 2的活性，并描绘生物学特性。 GCN 2瓜氨酸在SMC中的作用。在目标3中，我们将确定 AAA中GCN 2激活的影响，利用转基因（SMC特异性GCN 2敲除小鼠）和 饮食干预方法（限制蛋氨酸用于治疗既存AAA病变）。的 成功完成拟议的研究不仅将揭示一种内在的保护机制， SMC变性和AAA发病机制，而且还可能通过GCN 2激活提供新的范例。 饮食限制有效预防和干预AAA。

项目成果

Dietary therapy in abdominal aortic aneurysm - Insights from clinical and experimental studies.

• DOI: 10.3389/fcvm.2022.949262
• 发表时间: 2022
• 期刊: FRONTIERS IN CARDIOVASCULAR MEDICINE
• 影响因子: 3.6
• 作者: Yin, Li;Gregg, Alexander Christopher;Riccio, Alessandra Marie;Hoyt, Nicholas;Islam, Zain Hussain;Ahn, Jungeun;Le, Quang;Patel, Paranjay;Zhang, Mengxue;He, Xinran;McKinney, Matthew;Kent, Eric;Wang, Bowen
• 通讯作者: Wang, Bowen

Progress in murine models of ruptured abdominal aortic aneurysm.

• DOI: 10.3389/fcvm.2022.950018
• 发表时间: 2022
• 期刊: FRONTIERS IN CARDIOVASCULAR MEDICINE
• 影响因子: 3.6
• 作者: Yin, Li;Kent, Eric William;Wang, Bowen
• 通讯作者: Wang, Bowen