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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：
10396040
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/10396040
关键词：
Acetylation 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 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高血压和心血管疾病中起着关键作用，与失活相关。线粒体脱乙酰酶Sirt 3，但靶向治疗是不可用的。Sirt 3失活诱导抑制线粒体超氧化物歧化酶（SOD 2）并损害脂肪酸代谢，导致线粒体氧化应激和形成有害的脂质过氧化产物，异evuglandins（isoLG）。我们建议- Sirt 3失活和线粒体isoLG之间的正向循环促进血管功能障碍和高血压。我们开发了一种新的靶向异LG清除剂mito 2 HOBA，它可以保护Sirt 3的活性，高血压在这个建议中，我们将通过定义线粒体isoLG在细胞内的新作用来推进这项研究。 Sirt 3失活和血管功能障碍，我们将建立靶向线粒体的治疗潜力，异LG。我们的总体目标是确定isoLG介导的Sirt 3失活的具体机制，并直接检测使用新的转基因小鼠、新的靶向线粒体异LG的治疗潜力药物和原发性高血压患者的血管组织。我们将努力实现以下目标：目的1.验证内皮细胞Sirt 3失活诱导内皮细胞功能障碍的假说，通过针对线粒体isoLG。在这个目标中，我们将研究内皮细胞的病理生理作用，内皮特异性Sirt 3缺失（EcSirt 3 KO）和野生型中的Sirt 3损伤和线粒体isoLG 雄性和雌性小鼠。我们将明确Sirt 3失活和线粒体isoLG在内皮细胞中的作用。炎症、细胞衰老、内皮屏障破坏和松弛受损。目的2.验证平滑肌Sirt 3失活导致血管功能障碍的假设，线粒体isoLG改善血管功能。我们将研究平滑肌Sirt 3损伤的作用在平滑肌Sirt 3缺失（SmcSirt 3 KO）小鼠中。SOD 2-K68乙酰化和代谢的特定作用将在可用的SOD 2-脱乙酰化模拟物SOD 2K 68 R和Sirt 3-/--SODK 68 R小鼠中测试功能障碍。的将确定线粒体isoLG在平滑肌肥大、炎症和主动脉重塑中的作用。 AIM 3.在小鼠模型中确定靶向Sirt 3失活和线粒体isoLG的治疗潜力和原发性高血压患者的人体血管组织。我们将测试（A）是否用新的高血压发作后，靶向isoLG清除剂，如mito 2 HOBA，增加Sirt 3 （B）如果靶向血管中的线粒体isoLG，来自高血压人类受试者的离体组织减少炎症、改善Sirt 3活性和松弛。我们处于一个理想的位置来进行这些跨学科的研究。我们培育了一种新的Sirt 3转基因小鼠模型和靶向治疗。我们有机会接触到人体血管组织和独特的专业知识氧化应激、人体血管研究和高血压。我们的数据支持这种新的血管通路，这项工作有可能对新的临床治疗方法的发展产生重大影响。