The role of TFEB in aortic aneurysms

TFEB 在主动脉瘤中的作用

• 批准号: 10199015
• 负责人: Yanbo Fan
• 金额: $ 53.8万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199015
• 关键词: Abdominal Aortic Aneurysm; Amino Acids; Aneurysm; Animal Model; Animals; Anti-Inflammatory Agents; Aortic Aneurysm; ApoE knockout mouse; Apolipoprotein E; Apoptosis; Atherosclerosis; Autophagocytosis; Bioavailable; Biogenesis; Blood Vessels; Cardiovascular Diseases; Cell physiology; Clinical; Conjugated Linoleic Acids; Dependence; Detection; Diabetes Mellitus; Experimental Models; Fatty Acids; Foundations; Functional disorder; Histidine; Homeostasis; Human; Impairment; In Vitro; Inflammation; Intervention; Knock-out; Lead; Life; Linoleic Acids; Lipids; MMP2 gene; Metabolic Diseases; Methodology; Modeling; Mus; Nitrites; Nitrogen Dioxide; Nuclear Translocation; Operative Surgical Procedures; Oral; Pathologic; Patients; Pharmacology; Phase II Clinical Trials; Physiological; Plasma; Prevention; Production; Proteins; Research; Role; Rupture; Signal Transduction; Smooth Muscle Myocytes; Solid; Stimulus; Supplementation; Testing; Therapeutic; Transcriptional Activation; Translations; Vascular Diseases; Vascular Smooth Muscle; base; clinically relevant; human model; in vivo; inhibitor/antagonist; lipidomics; metabolomics; mortality; mouse model; nanomolar; new therapeutic target; nitration; nitroalkene; novel; novel strategies; novel therapeutic intervention; prevent; protective effect; transcription factor

ABSTRACT Abdominal Aortic aneurysm (AAA) results in very high mortality upon rupture. To date, besides surgical intervention –with only 10% of patients eligible-, no alternative therapeutic approaches are available. Therefore, it would be of high significance to identify novel strategies to effectively treat or prevent AAA in vivo. Vascular smooth muscle cells (VSMCs) are crucial in maintaining vascular wall integrity and function and VSMC homeostasis is disrupted in AAA. Transcription factor-EB (TFEB) is a “master” regulator of lysosomal biogenesis and autophagy. However, the role of TFEB in VSMC functions and AAA formation remain to be explored. We demonstrated that TFEB inhibits apoptosis, MMP2/9 activity and inflammation in VSMCs. VSMC specific TFEB knockout (KO) significantly aggravates vascular wall matrix degradation in a mouse AAA model. Nitroalkene derivatives of fatty acids such as oleic (OA-NO2) and linoleic acid (LNO2) have profound protective effects against cardiovascular and metabolic diseases. Conjugated linoleic acid (CLA) was identified as the preferential and major nitrated endogenous fatty acid and is readily bioavailable in humans and experimental models upon oral delivery of CLA and inorganic nitrite (NO2), making it an attractive intervention for CVD. We found that nitro-CLA protects against AAA formation in the Ang II-induced AAA mouse model and inhibits VSMC inflammation and apoptosis in a TFEB-dependent manner. It also promotes TFEB nuclear translocation in vitro in an H148-dependent fashion suggesting that TFEB is a direct target of nitro-CLA. Based on these evidences, we will test the central hypothesis that activation of TFEB by enhancing the endogenous production of nitro-CLA protects against AAA formation through inhibition of VSMC dysfunction. By taking advantage of our unique animal models generated specifically for these studies and the combined expertise of the assembled team, we propose 3 aims. Aim 1: Characterize the protective role of VSMC TFEB in AAA formation. We will test our working sub-hypothesis that VSMC TFEB protects against AAA formation through inhibition of VSMC dysfunction. Aim 2: Determine that activation of TFEB by nitro-CLA inhibits VSMC dysfunction in vitro. The working sub-hypothesis is that nitro-CLA prevents VSMC dysfunction in a TFEB-dependent manner. Aim 3: Define TFEB as a novel therapeutic target for nitro-CLA inhibition of AAA formation in vivo. The working sub- hypothesis is that endogenous production of nitro-CLA protects against AAA formation through activation of VSMC TFEB. In summary, we will characterize the protective role of TFEB in AAA formation and establish nitro-CLA as a novel therapeutic strategy against AAA by targeting VSMC TFEB. This mechanistic research will set a solid foundation for rapid translation into clinical utilization of nitro-CLA and may lead to a breakthrough for treatment or/and prevention of AAA.

抽象的 破裂后腹主动脉瘤（AAA）导致非常高的死亡率。迄今为止，除了手术 干预 - 只有10％的患者有资格 - 没有其他替代治疗方法。 因此，确定有效治疗或预防体内AAA的新型策略将具有很高的意义。 血管平滑肌细胞（VSMC）对于维持血管壁完整性和功能至关重要 VSMC稳态在AAA中被禁用。转录因子-EB（TFEB）是溶酶体的“主”调节剂 生物发生和自噬。但是，TFEB在VSMC函数和AAA形成中的作用仍然是 探索。我们证明TFEB抑制VSMC中的凋亡，MMP2/9活性和炎症。 VSMC 特定的TFEB敲除（KO）显着加剧了小鼠AAA模型中的血管壁基质降解。 脂肪酸（例如油酸（OA-NO2）和亚油酸（LNO2））的硝基烷衍生物具有深刻的保护 对心血管和代谢疾病的影响。共轭亚油酸（CLA）被确定为 优先和主要硝化的内源性脂肪酸，在人类和实验中很容易生物利用 口服CLA和无机亚硝酸盐（NO2）的模型，使其成为CVD的有吸引力的干预措施。我们 发现Nitro-CLA可预防ANG II诱导的AAA小鼠模型中的AAA形成并抑制 以TFEB依赖性方式注射VSMC和凋亡。它还促进TFEB核易位 以H148依赖性方式进行体外，这表明TFEB是硝基-CLA的直接靶标。基于这些 证据，我们将测试中心假设，即通过增强内源性生产来激活TFEB Nitro-CLA的含量可通过抑制VSMC功能障碍来防止AAA形成。通过利用 我们专门为这些研究生成的独特动物模型以及 组装团队，我们提出3个目标。目标1：表征VSMC TFEB在AAA组中的受保护作用。 我们将测试我们的工作子疗法，即VSMC TFEB通过抑制来防止AAA形成 VSMC功能障碍。 AIM 2：确定硝基-CLA激活TFEB会在体外抑制VSMC功能障碍。 工作子疗法的工作是硝基-CLA以TFEB依赖性方式阻止VSMC功能障碍。目的 3：将TFEB定义为硝基-CLA抑制AAA形成的新型治疗靶标。工作子 - 假设是内源性的硝基-CLA产生通过激活来防止AAA形成 VSMC TFEB。总而言之，我们将表征TFEB在AAA形成和建立中的受保护作用 Nitro-CLA是针对AAA的一种新型治疗策略，该策略是针对VSMC TFEB的。这项机械研究 将为快速转化为硝基-CLA的临床利用而为稳固的基础，并可能导致 治疗或/和预防AAA的突破。