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型糖尿病患者死亡总数的75%。高血压在糖尿病患者中发生的频率大约是非糖尿病患者的两倍。虽然很明显，糖尿病会增加心血管事件的风险，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 （PPAR3）和血管紧张素II (Ang II) 1型受体（AT1R）是肥胖症/糖尿病、高血压和心血管疾病（CVD）之间可能提供功能联系的两个关键决定因素。最近，我们报道了亚油酸（LNO2）和油酸（OA-NO2）的硝基衍生物在人体循环中的浓度超过1 <M，是有效的内源性ppar - γ配体。有趣的是，我们的初步研究首次证明了硝基烯不仅可以阻断Ang II与AT1R的结合，还可以抑制血管平滑肌细胞（VSMC）中AT1R的表达。此外，我们观察到外源性给予OA-NO2可降低小鼠血压。因此，硝基烯烃可能通过下调AT1R信号通路和激活VSMC中依赖ppar3的保护事件来发挥“血管和代谢保护”作用。在本研究中，我们将验证一个中心假设，即硝基烯是一种新的内源性分子，通过激活VSMC中的抗高血压和抗糖尿病信号通路来调节血压和高血压血管重构。具体来说，我们将：1)。确定oa - no2抑制AT1R信号通路的分子机制；2)。明确oa - no2介导的AT1R和PPAR3信号通路在VSMC增殖调控中的作用；3)。明确OA-NO2-介导的AT1R和PPAR3信号通路在调节血压和高血压血管重构中的作用。这些目标的成功实施将有助于更好地理解模型硝基烯OA-NO2在血管中的内源性信号传导作用，并为合理设计药物和开发具有降压和降糖特性的硝基烯衍生物奠定新的视角。

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.