Sirtuin 3 Inactivation and SOD2 Acetylation in Vascular Dysfunction and Hypertension

Sirtuin 3 失活和 SOD2 乙酰化在血管功能障碍和高血压中的作用

基本信息

批准号：
10593055
负责人：
Sergey Dikalov
金额：
$ 60.46万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-21 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593055
关键词：
Acetylation Aorta Arteries Attenuated Blood Vessels Cardiovascular Diseases Cell Aging Cell physiology Cessation of life Clinical Treatment Data Deacetylase Deacetylation Development Drug Targeting Endothelium Essential Hypertension Female Functional disorder Heart failure Human Hypertension Hypertrophy Impairment Inflammation Interdisciplinary Study Lipid Peroxidation Lysine Mediating Metabolic dysfunction Mitochondria Molecular Mus Myocardial Infarction Organ Oxidative Stress Pathogenesis Pathway interactions Patients Play Polyunsaturated Fatty Acids Positioning Attribute Relaxation Research Role SOD2 gene Sirtuins Smooth Muscle Smooth Muscle Myocytes Stroke Superoxide Dismutase Testing Therapeutic Tissues Transgenic Mice Vascular Diseases Vasodilation Viscosity Work antioxidant enzyme arteriole cytotoxic endothelial dysfunction fatty acid metabolism human subject hypertensive improved innovation insight male mimetics mitochondrial dysfunction mitochondrial metabolism mouse model muscle hypertrophy new therapeutic target novel novel therapeutics peroxidation prevent therapeutic evaluation vascular inflammation

项目摘要

Project Summary Vascular dysfunction plays a key role in hypertension and cardiovascular disease associated with inactivation of mitochondrial deacetylase Sirt3, but mitochondria-targeted treatments are not available. Sirt3 inactivation induces inhibition of mitochondrial superoxide dismutase (SOD2) and impairs fatty acid metabolism leading to mitochondrial oxidative stress and formation of harmful lipid peroxidation products, isolevuglandins (isoLG). We suggest that a feed- forward cycle between Sirt3 inactivation and mitochondrial isoLG promotes vascular dysfunction and hypertension. We developed new mitochondria-targeted isoLG scavenger, mito2HOBA, which protects Sirt3 activity and attenuates hypertension. In this proposal, we will advance this research by defining the novel role of mitochondrial isoLG in Sirt3 inactivation and vascular dysfunction, and we will establish the therapeutic potential of targeting mitochondrial isoLG. Our overall objective is to define the specific mechanism of isoLG-mediated Sirt3 inactivation and directly test the therapeutic potential of targeting mitochondrial isoLG using new transgenic mice, new mitochondria-targeted drugs, and vascular tissue from patients with essential hypertension. We will pursue the following aims: AIM 1.Test the hypothesis that inactivation of endothelial Sirt3 induces endothelial dysfunction which is prevented by targeting mitochondrial isoLG. In this aim we will examine the pathophysiological role of endothelial Sirt3 impairment and mitochondrial isoLG in endothelium specific Sirt3 depleted (EcSirt3KO) and wild-type male and female mice. We will define the role of Sirt3 inactivation and mitochondrial isoLG in endothelial inflammation, cell senescence, endothelial barrier disruption, and impaired relaxation. AIM 2.Test the hypothesis that inactivation of smooth muscle Sirt3 induces vascular dysfunction, and blocking mitochondrial isoLG improves vascular function. We will study the role of smooth muscle Sirt3 impairment in smooth muscle Sirt3 depleted (SmcSirt3KO) mice. The specific roles of SOD2-K68 acetylation and metabolic dysfunction will be tested in available SOD2-deacetylation mimetic SOD2K68R and Sirt3-/--SODK68R mice. The role of mitochondrial isoLG in smooth muscle hypertrophy, inflammation and aortic remodeling will be defined. AIM 3. Determine the therapeutic potential of targeting Sirt3 inactivation and mitochondrial isoLG in mouse models and human vascular tissue from patients with essential hypertension. We will test (A) if treatment with novel mitochondria-targeted isoLG scavengers, such as mito2HOBA, after onset of hypertension increases Sirt3 activity and improves vascular function in mouse models, and (B) if targeting mitochondrial isoLG in vascular tissues from hypertensive human subjects ex vivo reduces inflammation, improves Sirt3 activity, and relaxation. We are in an ideal position to perform these interdisciplinary studies. We developed new Sirt3 transgenic mouse models and mitochondria-targeted treatments. We have access to human vascular tissue and unique expertise in oxidative stress, human vascular studies and hypertension. Our data support this novel pathway in vascular dysfunction, and this work has the potential to make a major impact on the development of new clinical treatments.

项目摘要血管功能障碍在与失活有关的高血压和心血管疾病中起关键作用线粒体脱乙酰基酶SIRT3，但无法使用线粒体靶向治疗。 SIRT3失活引起抑制线粒体超氧化物歧化酶（SOD2）并损害脂肪酸代谢导致线粒体氧化应激和有害脂质过氧化产物的形成，异甲列蛋白（Iselg）。我们建议饲料 SIRT3失活和线粒体ISLEG之间的正向周期促进了血管功能障碍和高血压。我们开发了新的线粒体靶向的Iselg清道夫Mito2Hoba，它保护了SIRT3活动并减弱高血压。在此提案中，我们将通过定义线粒体隔离在中的新作用来推进这项研究 SIRT3失活和血管功能障碍，我们将建立靶向线粒体的治疗潜力分离。我们的总体目的是定义Isalg介导的SIRT3失活的特定机制，并直接测试使用新的转基因小鼠靶向线粒体分离的治疗潜力，新的线粒体靶向药物和来自基本高血压患者的血管组织。我们将追求以下目标：目的1.检验假设内皮SIRT3失活会诱导内皮功能障碍通过靶向线粒体分离。在此目标中，我们将研究内皮的病理生理作用 sirt3损伤和内皮特异性SIRT3中的线粒体隔离（ECSIRT3KO）和野生型雄性和雌鼠。我们将定义SIRT3失活和线粒体隔离的作用炎症，细胞衰老，内皮屏障破坏和放松受损。目标2.检验假设平滑肌SIRT3造成血管功能障碍并阻塞线粒体分离可改善血管功能。我们将研究平滑肌SIRT3损伤的作用在平滑肌中，SIRT3耗尽（SMCSIRT3KO）小鼠。 SOD2-K68乙酰化和代谢的特定作用功能障碍将在可用的SOD2-二乙基化模拟SOD2K68R和SIRT3 - / - SODK68R小鼠中进行测试。这线粒体隔离在平滑肌肥大，炎症和主动脉重塑中的作用将定义。 AIM 3。确定靶向SIRT3失活和线粒体分离的治疗潜力和患有基本高血压患者的人血管组织。如果新颖的治疗，我们将测试（a）高血压发作后，线粒体靶向的Iselg清道夫（例如Mito2Hoba）增加了SIRT3 活性并改善小鼠模型中的血管功能，（b）如果靶向线粒体分离高血压人体受试者的组织可减少炎症，改善SIRT3活性和放松。我们处于执行这些跨学科研究的理想位置。我们开发了新的SIRT3转基因鼠标模型和线粒体靶向治疗。我们可以使用人类血管组织和独特的专业知识在氧化应激中，人血管研究和高血压。我们的数据支持这一新颖的血管中的途径功能障碍，这项工作有可能对新临床治疗的发展产生重大影响。