Sirtuin 3 Impairment and SOD2 Acetylation in Oxidative Stress and Hypertension

氧化应激和高血压中的 Sirtuin 3 损伤和 SOD2 乙酰化

• 批准号: 9130252
• 负责人: Sergey Dikalov
• 金额: $ 39.5万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-21 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130252
• 关键词: Acetylation; Acetyltransferase; Affect; Aging; Angiotensin II; Antihypertensive Agents; Antioxidants; Blood; Blood Pressure; Blood Vessels; DOCA; Data; Deacetylase; Disease; Endothelium; Genetic; Health; Heart; Heart failure; Human; Hypertension; Hypotension; Impairment; Incidence; Lead; LoxP-flanked allele; Lysine; MYH11 gene; Measures; Mitochondria; Molecular; Mus; Myocardial Infarction; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Positioning Attribute; Risk Factors; Role; SOD2 gene; Societies; Stroke; Superoxide Dismutase; Superoxides; TNF gene; Testing; Therapeutic; Therapeutic Agents; Tissues; Transgenic Mice; Vascular Diseases; Vascular Smooth Muscle; Vasodilation; Wild Type Mouse; Work; antioxidant enzyme; blood pressure reduction; design; genetic manipulation; hypertension treatment; improved; innovation; mimetics; mitochondrial dysfunction; model design; mouse model; novel; novel therapeutics; overexpression; prevent; response; salt sensitive hypertension; targeted treatment; vascular endothelial dysfunction

 DESCRIPTION (provided by applicant): Hypertension is a major health problem in Western Societies and a risk factor for stroke, myocardial infarction, and heart failure. Blood pressure of many hypertensive patients remains poorly controlled despite treatment with multiple drugs, likely due to additional mechanisms contributing to hypertension that are unaffected by current treatments. Recently, we have defined novel role of mitochondrial superoxide (O2•) in hypertension. We have shown that genetic manipulation of mitochondrial antioxidant enzyme superoxide dismutase (SOD2) affects blood pressure. In the proposed studies, we will take this work forward by defining a new mechanism of mitochondrial dysfunction. Our preliminary data indicate that SOD2 becomes hyperacetylated due to a decline in activity of the key mitochondrial deacetylase Sirtuin 3 (Sirt3). We propose that reduced Sirt3 activity and SOD2 hyperacetylation contribute to oxidative stress and hypertension, and that measures to increase Sirt3 activity will prevent vascular dysfunction and reduce hypertension. This novel concept may lead to a paradigm-shift in defining Sirt3 as a new target in the treatment of hypertension. The overall objective of this proposal is to investigate the specific molecular mechanisms of Sirt3 impairment and SOD2 hyperacetylation, define their contribution to hypertension and to identify potential therapeutic approaches to reduce this phenomenon. We will pursue the following aims: AIM 1. To determine the role of tissue specific Sirt3 impairment in vascular oxidative stress and hypertension. In this aim we will examine the specific roles of Sirt3 in mice with Sirt3 depletion n endothelium (EcSirt3 KO) or vascular smooth muscle (SmcSirt3 KO) in vascular oxidative stress using angiotensin II and DOCA-salt induced hypertension, and compare with Sirt3-/- and wild-type mice. AIM 2. To determine the molecular mechanisms of reduced Sirt3 deacetylase activity and SOD2 hyper- acetylation in oxidative stress in response to angiotensin II and TNFa. Specifically, we will define the mechanisms of Sirt3 inactivation and the role of lysine acetyltransferase GCN5L1 in SOD2 hyperacetylation, O2• overproduction and impairment of endothelium dependent vasodilatation. AIM 3. To study if Sirt3 overexpression and SOD2 mimetics reduce vascular oxidative stress and inhibit hypertension. In this aim we will test the hypothesis that genetic Sirt3 overexpression or scavenging of downstream mitochondrial O2• by new SOD2 mimetics will improve Sirt3 function, protect from vascular oxidative stress and inhibit Ang II and DOCA-salt induced hypertension. We are in an ideal position to perform these studies. We have developed unique transgenic mouse models and designed new mitochondria-targeted SOD2 mimetics to rescue vascular function in Sirt3 impairment. We have exclusive expertise in oxidative stress, hypertension, mitochondria-targeted antioxidants, mitochondrial and vascular studies. This work has the potential of providing a new understanding and treatment for this disease. Of note, our new SOD2 mimetics could be used as novel therapeutic agents in humans.

 描述（由应用提供）：高血压是西方社会的主要健康问题，也是中风，心肌梗塞和心力衰竭的危险因素。血压的 许多高血压患者对多种药物的控制目的地治疗仍然很差，这可能是由于导致高血压的其他机制引起的，这些机制不受当前治疗的影响。最近，我们定义了线粒体超氧化物（O2•）在高血压中的新作用。我们已经表明，线粒体抗氧化酶超氧化物歧化酶（SOD2）的遗传操纵会影响血压。在拟议的研究中，我们将通过定义线粒体功能障碍的新机制来实现这项工作。我们的初步数据表明，由于关键线粒体脱乙酰基酶Sirtuin 3（SIRT3）的活性下降，SOD2被过度乙酰化。我们建议降低SIRT3活性和SOD2高乙酰化有助于氧化应激和高血压，并且增加SIRT3活性的措施将防止血管功能障碍并降低高血压。这个新颖的概念可能会导致将SIRT3定义为高血压治疗的新目标，从而导致范式转移。该提案的总体目的是研究SIRT3损伤和SOD2高乙酰化的特定分子机制，定义它们对高血压的贡献，并确定潜在的治疗方法来减少这种现象。我们将追求以下目标：目标1。确定组织特异性SIRT3损伤在血管氧化应激和高血压中的作用。在此目的中，我们将使用SIRT3部署N内皮（ECSIRT3 KO）或血管平滑肌（SMCSIRT3 KO）在血管氧化应激中使用血管紧张素II和DOCA-SALT诱导的高血压，并与SIRT3 - / - / - / - / - 和野生型和野生型小鼠相比。目的2。确定氧化应激中SIRT3脱乙酰基酶活性的分子机制和SOD2高乙酰化对血管紧张素II和TNFA的反应。具体而言，我们将定义SIRT3失活的机制以及赖氨酸乙酰转移酶GCN5L1在SOD2高乙酰化，O2，O2•过量生产和依赖内皮依赖性血管静脉的作用。目的3。研究SIRT3过表达和SOD2 Mimetics是否减少了血管氧化应激并抑制高血压。在此目的中，我们将检验以下假设：遗传SIRT3过表达或清除下游线粒体O2•通过新的SOD2 Mimetics通过新的SIRT3功能，可以改善SIRT3功能，免受血管氧化应激，并抑制ANG II和DOCA-SALT诱导的高血压。我们处于执行这些研究的理想位置。我们开发了独特的转基因小鼠模型，并设计了新的线粒体靶向SOD2 Mimetics来挽救SIRT3损伤中的血管功能。我们在氧化应激，高血压，线粒体靶向抗氧化剂，线粒体和血管研究方面具有专业知识。这项工作有可能为这种疾病提供新的理解和治疗。值得注意的是，我们的新SOD2 Mimetics可以用作人类的新型治疗剂。