Role of Nrf2 in Vascular Antioxidant Defense

 描述(申请人提供)：血管氧化应激是多种心血管疾病的共同特征，但基于给予抗氧化剂的治疗方法令人惊讶地令人失望。因此，对直接投资的兴趣与日俱增 在与氧化应激相关的病理条件下，上调内源性抗氧化剂防御作为一种潜在的治疗策略。这些策略的一个吸引人的靶点是主要的抗氧化剂和细胞保护转录因子核因子(红系衍生2)样蛋白2(NRF2)，它调节多种抗氧化剂和细胞保护基因的表达，这些基因可能与200多种不同的人类疾病有关。该项目将使用一种新的强大的实验模型(NRF2(-/-)基因敲除大鼠)来检验总体假设，即NRF2调节的酶的下调在高盐(HS)饮食发生的血管氧化应激中起主要作用；防止盐诱导的Ang II抑制或给予已知上调NRF2系统的化合物将改善与饮食盐摄入量增加相关的内皮功能障碍和受损的血管生成。具体目的1是验证恢复正常血浆Ang II水平和应用MAS受体激动剂通过共同途径(ERK1/2激活)改善HS喂养动物的血管氧化应激和内皮功能障碍，从而激活NRF2抗氧化防御系统的假设。具体目的#2是验证一种假设，即恢复正常的血浆Ang II水平和给予MAS受体激动剂通过共同的途径(ERK1/2激活)防止盐诱导的微血管稀疏，导致NRF2介导的抗氧化防御机制上调；以及在盐诱导的Ang II抑制存在的情况下，直接上调NRF2系统将改善血管生成反应。鉴于了解心血管疾病中与性别相关的差异的重要性，以及关于雌性NRF2抗氧化防御的信息相对匮乏，我们扩大了研究范围，包括雄性和雌性大鼠。由于NRF2在调节抗氧化防御中的普遍重要性，这些研究将为盐诱导的氧化应激和血管功能障碍的机制提供有价值的见解；并可能导致基于NRF2调节的抗氧化防御机制的直接上调而开发有效的心血管疾病治疗方法。

 DESCRIPTION (provided by applicant): Vascular oxidant stress is a common feature of multiple cardiovascular diseases, but therapeutic approaches based on administration of antioxidants have been surprisingly disappointing. As a result, there is growing interest in direct upregulation of endogenous antioxidant defenses as a potential therapeutic strategy in pathological conditions associated with oxidant stress. One attractive target for these strategies is the master antioxidant and cell protective transcription factor nuclear factor (erythroid- derivd 2)-like-2 (NRF2), which regulates the expression of multiple antioxidant and cell protective genes that are potentially involved in over 200 different human diseases. This project will use a new and powerful experimental model (the Nrf2(-/-) knockout rat) to test the overall hypothesis that down-regulation of NRF2-regulated enzymes plays a major role in vascular oxidant stress occurring with high salt (HS) diet; and that prevention of salt-induced ANG II suppression or administration of compounds known to upregulate the NRF2 system will ameliorate the endothelial dysfunction and impaired angiogenesis associated with elevated dietary salt intake. Specific Aim #1 is to test the hypothesis that restoring normal plasma ANG II levels and administration of mas receptor agonists ameliorate vascular oxidant stress and endothelial dysfunction in HS-fed animals via a common pathway (ERK 1/2 activation), leading to activation of the NRF2 antioxidant defense system. Specific Aim #2 is to test the hypothesis that restoration of normal plasma ANG II levels and administration of mas receptor agonists prevent salt-induced microvascular rarefaction via a common pathway (ERK 1/2 activation), leading to upregulation of NRF2-mediated antioxidant defense mechanisms; and that direct upregulation of the NRF2 system will improve angiogenic responses in the presence of salt-induced ANG II suppression. We have expanded the study to include male and female rats in light of the importance of understanding sex-related differences in cardiovascular disease and the relative scarcity of information regarding NRF2 antioxidant defenses in females. Because of the pervasive importance of NRF2 in regulating antioxidant defenses, these studies will provide valuable insight into the mechanisms of salt-induced oxidant stress and vascular dysfunction; and could lead to the development of effective therapeutic approaches to cardiovascular diseases based on direct upregulation of NRF2-regulated antioxidant defense mechanisms.