Nitroalkenes and Blood Pressure Regulation

描述（由申请人提供）：有充分的证据表明，糖尿病的心血管并发症占2型糖尿病患者所有死亡的75%。糖尿病患者发生高血压的频率约为非糖尿病患者的两倍。虽然糖尿病状态明显增加了心血管事件的风险，但代谢紊乱影响血管功能和结构的机制仍有待进一步确定。新出现的数据表明，过氧化物酶体增殖物激活受体3（PPAR 3）和血管紧张素II（Ang II）1型受体（AT 1 R）是两个关键的决定因素，可能提供肥胖/糖尿病，高血压和心血管疾病（CVD）之间的功能联系。最近，我们已经报道了鉴定亚油酸（LNO 2）和油酸（OA-NO2）的硝基烯烃衍生物，其在人体循环中的浓度超过1 μ M，作为有效的内源性PPAR-gamma配体。有趣的是，我们的初步研究首次证明，硝基烯烃不仅可以阻断血管紧张素Ⅱ与AT 1 R的结合，而且还可以抑制血管平滑肌细胞（VSMC）AT 1 R的表达。此外，我们还观察到外源性给予OA-NO2可降低小鼠的血压。因此，硝基烯烃可以通过下调AT 1 R信号通路和激活VSMC中的PPAR 3依赖性保护事件的组合来发挥“血管和代谢保护”作用。在这个建议中，我们将测试的中心假设，硝基烯烃是新的内源性分子，调节血压和高血压血管重塑，通过激活抗高血压和抗糖尿病的信号通路在VSMC。具体而言，我们将：1）。确定OA-NO2-抑制AT 1 R信号通路的分子机制; 2）.明确OA-NO2介导的AT 1 R和PPAR 3信号通路在VSMC增殖调控中的作用; 3）.明确OA-NO2介导的AT 1 R和PPAR 3信号通路在血压调节和高血压血管重塑中的作用。这些目标的成功实施将导致更好地理解模型硝基烯烃，OA-NO2，在血管系统中的内源性信号传导作用，并将为合理的药物设计和开发具有抗高血压和抗糖尿病特性的硝基烯烃衍生物的新观点奠定坚实的基础。 项目叙述：有充分的证据表明，糖尿病的心血管并发症占2型糖尿病患者死亡的75%。糖尿病患者发生高血压的频率约为非糖尿病患者的两倍。虽然糖尿病状态明显增加了心血管事件的风险，但代谢紊乱影响血管功能和结构的机制仍有待进一步确定。这一建议的成功实施，将导致更好地了解血管系统中的硝基烯烃的内源性信号传导作用，并将设置强有力的基础上，合理的药物设计和开发的硝基烯烃衍生物的抗高血压和抗糖尿病性能的新观点。

DESCRIPTION (provided by applicant): It has been well documented that cardiovascular complications of diabetes account for 75% of all deaths in patients with type 2 diabetes. Hypertension occurs approximately twice as frequently in patients with diabetes compared with non-diabetic individuals. Although it is clear that the state of diabetes confers an increased risk of cardiovascular events, the mechanism by which metabolic perturbations influence vascular function and structure remain to be further defined. Emerging data suggest that peroxisome proliferator-activated receptor-3 (PPAR3) and angiotensin II (Ang II) type 1 receptor (AT1R) are two critical determinants that may provide functional links between obesity/diabetes, hypertension and cardiovascular disease (CVD). Recently, we have reported the identification of nitroalkene derivatives of linoleic acid (LNO2) and oleic acid (OA-NO2) with concentrations exceeding 1 <M in the human circulation, as potent endogenous PPAR-gamma ligands. Intriguingly, our preliminary studies have demonstrated for the first time that nitroalkenes not only can block Ang II binding to AT1R, but also suppress the AT1R expression in vascular smooth muscle cells (VSMC). In addition, we have observed that exogenous administration of OA-NO2 decreases blood pressure in mice. Therefore, nitroalkenes may exert "vascular and metabolic protective" effects through a combination of down- regulation of the AT1R signaling pathway and activation of PPAR3-dependent protective events in VSMC. In this proposal, we will test the central hypothesis that nitroalkenes are novel endogenous molecules that regulate blood pressure and hypertensive vascular remodeling by activating antihypertensive and antidiabetic signaling pathways in VSMC. Specifically, we will: 1). Determine the molecular mechanisms of OA-NO2-inhibition of the AT1R signaling pathway; 2). Define the contributory roles of OA-NO2-mediated AT1R and PPAR3 signaling pathways in the regulation of VSMC proliferation; 3). Define the contributory roles of OA-NO2- mediated AT1R and PPAR3 signaling pathways in the regulation of blood pressure and hypertensive vascular remodeling. The successful implementation of these goals should lead to a better understanding of endogenous signaling actions of the model nitroalkene, OA-NO2, in the vasculature and will set strong basis for new perspectives on rational drug design and development of nitroalkene derivatives with antihypertensive and antidiabetic properties. Project Narrative: It has been well documented that cardiovascular complications of diabetes account for 75% of all deaths in patients with type 2 diabetes. Hypertension occurs approximately twice as frequently in patients with diabetes compared with non-diabetic individuals. Although it is clear that the state of diabetes confers an increased risk of cardiovascular events, the mechanism by which metabolic perturbations influence vascular function and structure remain to be further defined. The successful implementation of this proposal should lead to a better understanding of endogenous signaling actions of nitroalkenes in the vasculature and will set strong basis for new perspectives on rational drug design and development of nitroalkene derivatives with antihypertensive and antidiabetic properties.