Sirtuin 3 Impairment and SOD2 Acetylation in Oxidative Stress and Hypertension

 描述(申请人提供)：高血压是西方社会的一个主要健康问题，也是中风、心肌梗死和心力衰竭的危险因素。血压，血压 许多高血压患者尽管接受了多种药物的治疗，但控制仍然很差，这可能是由于导致高血压的其他机制不受当前治疗方法的影响。最近，我们明确了线粒体超氧化物歧化酶(O2·)在高血压中的新作用。我们已经证明，线粒体抗氧化酶超氧化物歧化酶(SOD2)的遗传操作会影响血压。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推进这项工作。我们的初步数据表明，由于关键的线粒体脱乙酰酶Sirtuin3(SIRT3)活性下降，SOD2变得过度乙酰化。我们认为，SIRT3活性降低和SOD2高乙酰化有助于氧化应激和高血压，而提高SIRT3活性的措施将防止血管功能障碍，降低高血压。这一新的概念可能导致将SIRT3定义为高血压治疗的新靶点的范式转变。该提案的总体目标是研究SIRT3损伤和SOD2高乙酰化的具体分子机制，确定它们在高血压中的作用，并寻找潜在的治疗方法来减少这一现象。我们将追求以下目标：目的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。为此，我们将利用血管紧张素II和DOCA盐诱导的高血压，研究SIRT3在内皮细胞SIRT3缺失(EcSirt3KO)或血管平滑肌(SmcSirt3KO)缺失的小鼠血管氧化应激中的具体作用，并与SIRT3-/-和野生型小鼠进行比较。目的2.探讨血管紧张素II和肿瘤坏死因子α诱导的氧化应激过程中SIRT3脱乙酰酶活性降低和SOD2高乙酰化的分子机制。具体地说，我们将确定SIRT3失活的机制以及赖氨酸乙酰转移酶GCN5L1在SOD2超乙酰化、O2·过量产生和内皮依赖性血管扩张障碍中的作用。目的3.研究SIRT3过表达和SOD2类似物是否能降低血管氧化应激，抑制高血压。为此，我们将验证一种假设，即基因SIRT3的过度表达或通过新的SOD2模拟物清除下游线粒体O2·将改善SIRT3的功能，保护血管免受氧化应激，并抑制Ang II和DOCA-SALT诱导的高血压。我们处于进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模拟物来挽救SIRT3损伤的血管功能。我们在氧化应激、高血压、针对线粒体的抗氧化剂、线粒体和血管研究方面拥有独一无二的专业知识。这项工作有可能为该病提供新的认识和治疗方法。值得注意的是，我们新的SOD2模拟物可以用作人类的新型治疗剂。

 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.