Sirtuin 3 Impairment and SOD2 Acetylation in Oxidative Stress and Hypertension

 描述（由申请人提供）：高血压是西方社会的主要健康问题，也是中风、心肌梗死和心力衰竭的危险因素。血压 尽管用多种药物治疗，许多高血压患者仍然控制不佳，这可能是由于导致高血压的其他机制不受当前治疗的影响。近年来，我们发现线粒体超氧阴离子（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（SOD 2）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Sirtuin 3（Sirt 3）的活性下降，SOD 2变得高度乙酰化。我们认为，降低Sirt 3活性和SOD 2的超乙酰化有助于氧化应激和高血压，而增加Sirt 3活性的措施将防止血管功能障碍和降低高血压。这一新概念可能导致将Sirt 3定义为高血压治疗新靶点的范式转变。该提案的总体目标是研究Sirt 3损伤和SOD 2超乙酰化的特定分子机制，确定其对高血压的贡献，并确定潜在的治疗方法来减少这种现象。我们将努力实现以下目标：目标1。确定组织特异性Sirt 3损伤在血管氧化应激和高血压中的作用。在这个目标中，我们将检查Sirt 3在内皮细胞Sirt 3缺失（EcSirt 3 KO）或血管平滑肌Sirt 3 KO（SmcSirt 3 KO）小鼠中的特定作用，使用血管紧张素II和DOCA-盐诱导的高血压血管氧化应激，并与Sirt 3-/-和野生型小鼠进行比较。 AIM 2.确定响应于血管紧张素II和TNF α的氧化应激中Sirt 3脱乙酰酶活性降低和SOD 2超乙酰化的分子机制。具体而言，我们将确定Sirt 3失活的机制和赖氨酸乙酰转移酶GCN 5L 1在SOD 2过度乙酰化，O2·过量产生和内皮依赖性血管舒张功能受损中的作用。 AIM 3.研究Sirt 3过表达和SOD 2模拟物是否降低血管氧化应激并抑制高血压。在这个目标中，我们将测试这样的假设，即遗传Sirt 3过表达或通过新的SOD 2模拟物清除下游线粒体O2·将改善Sirt 3功能，保护免受血管氧化应激并抑制Ang II和DOCA盐诱导的高血压。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，并设计了新的靶向SOD 2模拟物，以挽救Sirt 3损伤的血管功能。我们在氧化应激、高血压、靶向抗氧化剂、线粒体和血管研究方面拥有独家专业知识。这项工作有可能为这种疾病提供新的认识和治疗。值得注意的是，我们的新SOD 2模拟物可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.