Methionine Sulfoxide Reductase A: a Novel Molecular Determinant of Autonomic Reg

氧化应激是自主神经功能失调、血压升高和终末器官损伤的主要原因。 高血压的危害甲基亚砜还原酶A（Methylsulfonylreductase A，MsrA）是一种独特的抗氧化剂， 通过选择性逆转细胞中甲硫氨酸残基的氧化， proteins.我们推断，有针对性地预防蛋氨酸氧化可能会产生一种表型， 与一般抗氧化剂超氧化物歧化酶（SOD）、过氧化氢酶和谷胱甘肽有明显不同 过氧化物酶（GPx）。在初步实验中，我们发现MsrA-/-小鼠表现出自主神经失调， 交感神经活动（SNA）增加、高血压和主动脉瘤形成。这些表型 在SOD或GPx缺陷的小鼠中未观察到。虽然MsrA的五项保护行动 在衰老、神经退行性变和心肌缺血/梗死中证实，其在自主神经功能中的作用 调节、高血压和血管损伤尚未被研究。我们假设：1）MsrA是 所需的正常自主神经和血压调节，并防止血管紧张素II（Ang II）诱导的 高血压和终末器官损伤，通过终末器官和大脑的作用降低SNA;和2） 其机制包括抑制氧化应激和炎症。项目目标是：（1）确定 MsrA基因敲除小鼠、转基因小鼠和对照小鼠的心血管、自主神经和终末器官表型 （2）阐明靶向MsrA表达和缺失在血管生成中的作用， 在神经系统与血管肌肉中;和（3）确定氧化应激的CNS贡献， 炎症和肾素-血管紧张素系统增加SNA，高血压和终末器官损伤。 MsrR-/-小鼠。将充分表征心血管和自主神经表型。氧化性炎症 将在心脏、主动脉、肺动脉和肺动脉中测量应激、细胞因子和相关的促和抗氧化基因的表达 和特定的大脑部位将使用基因以组织和位点特异性方式修饰MsrA表达， MsrA和siRNA-MsrA的靶向和病毒介导的基因转移。将对中央机制进行评价 通过测量侧脑室注射抗氧化剂Tempol的反应， 阻滞剂氯沙坦和交感神经抑制药利美尼定。这种特异性蛋氨酸的重要性 还原酶作为一种新的自主活动和终末器官完整性的保护性调节剂， 作为治疗高血压的治疗靶点。 相关性（参见说明）： 氧化应激导致许多与年龄有关的疾病，包括高血压。发现MsrA 在神经系统和周围组织如动脉血管中发挥强大的保护作用 将其鉴定为自主调节和终末器官损伤新决定因素，以及潜在的治疗剂， 高血压的目标。

Oxidative stress is a major cause of autonomic dysregulation, increased blood pressure (BP) and end-organ damage in hypertension. Methionine sulfoxide reductase A (MsrA) is a unique anfioxidant that enables redox signaling and protects against oxidative damage by selectively reversing oxidation of methionine residues in proteins. We reasoned that the targeted prevention of methionine oxidation might yield a phenotype distinctively different than the general antioxidants superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx). In preliminary experiments, we found that MsrA-/- mice exhibit autonomic dysregulafion, increased sympathetic nerve activity (SNA), hypertension and aortic aneurysm formation. These phenotypes have not been observed in mice deficient in SOD or GPx. While protecfive actions of MsrA have been demonstrated in aging, neurodegeneration, and myocardial ischemia/infarcfion, its roles in autonomic regulation, hypertension and vascular damage have not been invesfigated. We hypothesize that: 1) MsrA is required for normal autonomic and BP regulation and protects against angiotensin II (Ang ll)-induced hypertension and end-organ damage via actions at both the end-organ and the brain to reduce SNA; and 2) the mechanisms include inhibition of oxidative stress and inflammation. Project aims are to: (1) Determine cardiovascular, autonomic and end-organ phenotypes in global MsrA knockout, transgenic and control mice before and during systemic infusion of Ang-ll; (2) Deflne the roles of targeted MsrA expression and deletion in nervous system vs. vascular muscle; and (3) Determine the CNS contributions of oxidative stress, inflammation, and the renin-angiotensin system to increased SNA, hypertension, and end-organ damage in MsrR-/- mice. Cardiovascular and autonomic phenotypes will be fully characterized. Inflammation, oxidative stress, cytokines and associated expression of pro- and antioxidant genes will be measured in heart, aorta and speciflc brain sites. MsrA expression will be modifled in a tissue- and site-speciflc manner using gene targeting and viral-mediated gene transfer of MsrA and siRNA-MsrA. Central mechanisms will be evaluated by measuring responses to intracerebroventricular infusions ofthe antioxidant tempol, the ATi receptor blocker losartan, and the sympatho-inhibitory drug rilmenidine. The signiflcance ofthis speciflc methionine reductase as a novel, protective regulator of autonomic activity and end-organ integrity relates to its potential as a therapeutic target for treatment of hypertension. RELEVANCE (See instructions): Oxidative stress contributes to many age-related diseases including hypertension. The finding that MsrA exerts powerful protective actions in the nervous system and peripheral tissues like arterial blood vessels identify it as a novel determinant of autonomic regulafion and end-organ damage, and a potenfial therapeufic target in hypertension.