Roles of oxidation and inflammation in aortic stiffening

描述（由申请人提供）：越来越明显的是，较大血管（特别是主动脉）的电容功能通过在心脏收缩期间调节一部分心搏量、降低心脏收缩压并在心脏舒张期间维持全身灌注来调节血液动力学。常见的临床病症，包括衰老、胰岛素抵抗、糖尿病和高血压本身与这种弹性功能的丧失有关，易患收缩期高血压。这些变化的机制尚不清楚;然而，临床研究表明，炎症和氧化损伤与动脉硬化参数相关。生物化学和实验研究也表明，活性氧物质参与了弹性蛋白和胶原蛋白的修饰，从而促进动脉硬化。我们实验室和其他实验室的先前工作表明，活性氧在高血压中起着关键作用。最近，我们已经表明，适应性免疫系统和细胞因子IL-17在高血压的发生中是重要的。在拟议的研究中，我们将采用独特的转基因小鼠，使我们能够增加或减少血管平滑肌活性氧水平，以研究这些如何有助于动脉硬化，血管胶原蛋白和弹性蛋白含量以及这些的生化修饰。我们将通过使用我们制造的小鼠来实现这一点，这些小鼠允许我们删除细胞外超氧化物歧化酶（SOD 3）或NADPH氧化酶亚基p22 phox。我们推测，通过删除SOD 3增加血管氧化损伤将增强，而通过删除p22 phox抑制氧化应激将防止动脉硬化。在其他研究中，我们将检验适应性免疫，特别是T细胞和细胞因子IL-17有助于动脉硬化的假设。我们认为RAG-1-/-和IL-17-/-小鼠在血管紧张素II输注过程中不会发生动脉硬化，但过继性T细胞转移会促进这些动物的动脉硬化。最后，我们假设动脉硬化通过将增加的压力传递到靶组织，如远端血管和肾脏，将促进炎症反应和T细胞活化，从而进一步增加血压。为了检验这一假设，我们将弹性蛋白缺乏症杂合子小鼠（Eln小鼠）与RAG-1-/-小鼠杂交。我们假设这些动物与Eln小鼠相比将具有降低的血压，并且T细胞的过继转移将恢复这些动物的血压。这些研究将为动脉硬化的病因学提供新的信息。我们在高血压生理学，结缔组织生物化学和心血管组织形态学方面的综合专业知识使我们处于追求这些研究方向的独特地位。 公共卫生相关性：项目叙述：动脉硬化是收缩期高血压的一个重要介质，然而大血管顺应性变化的机制尚不清楚。该项目将测试氧化损伤和适应性免疫系统相互作用增加动脉僵硬度的假设。这些研究有望提供关于高血压、血管疾病以及动脉顺应性改变如何易患炎症的新信息。

DESCRIPTION (provided by applicant): It has become increasingly apparent that the capacitance function of larger vessels, and in particular the aorta, modulates hemodynamics by accommodating a portion of stroke volume during systole, reducing systolic pressure and maintaining systemic perfusion during diastole. Common clinical conditions, including aging, insulin resistance, diabetes and hypertension per se are associated with loss of this elastance function, predisposing to systolic hypertension. The mechanisms underlying these changes remain unknown; however clinical studies have suggested that inflammation and oxidative injury are associated with parameters of arterial stiffening. Biochemical and experimental studies have also implicated reactive oxygen species in modifications of elastin and collagen that would promote arterial stiffening. Prior work from our laboratory and others demonstrated that reactive oxygen species play a critical role in hypertension. More recently, we have shown that the adaptive immune system and the cytokine IL-17 are important in the genesis of hypertension. In the proposed studies, we will employ unique, genetically modified mice that permit us to increase or decrease vascular smooth muscle levels of reactive oxygen species to study how these contribute to arterial stiffening, vascular collagen and elastin content and biochemical modifications of these. We will accomplish this by using mice we have made that allow us to delete either the extracellular superoxide dismutase (SOD3) or the NADPH oxidase subunit p22phox. We hypothesize that increasing vascular oxidant injury by deleting SOD3 will enhance, while inhibiting oxidant stress by deleting p22phox will prevent arterial stiffening. In other studies, we will test the hypothesis that adaptive immunity and in particular T cells and the cytokine IL-17 contribute to arterial stiffening. We propose that RAG-1-/- and IL-17-/- mice will not develop arterial stiffening during angiotensin II infusion, but that adoptive transfer of T cells will promote arterial stiffening in these animals. Finally, we hypothesize that arterial stiffening, by transmitting increased pressure to target tissues, such as distal vessels and the kidney; will promote an inflammatory response and T cell activation, which further increases blood pressure. To test this hypothesis, we will cross mice heterozygotic for elastin deficiency (Eln mice) with RAG-1-/- mice. We postulate that these animals will have reduced blood pressure compared to Eln mice, and that adoptive transfer of T cells will restore blood pressure in these animals. These studies will provide new information regarding the etiology of arterial stiffening. Our combined expertise in the physiology of hypertension, connective tissue biochemistry and cardiovascular histomorphology place us in a unique position to pursue these directions of research. PUBLIC HEALTH RELEVANCE: Project Narrative: Arterial stiffening is an important mediator of systolic hypertension; however the mechanisms responsible for changes in large vessel compliance remain undefined. This project will test the hypothesis that oxidative injury and the adaptive immune system interact to increase arterial stiffness. These studies promise to provide new information regarding hypertension, vascular disease and how alterations in arterial compliance predispose to inflammation.