Mechanisms of Stress-Induced Cardiovascular Reactivity in Rats

项目总结：我们已经建立了Dahl盐敏感(DS)大鼠的行为应激模型 这表明，活性氧(ROS)参与了应激引起的血压升高。我们 曾假设应激通过涉及内皮素(ET)和/或 血管紧张素II途径通过激活NADPH氧化酶和解偶联一氧化氮合酶。项目2‘S BP应力 一群年轻人表明，肥胖者对压力的反应明显更强。 或社会经济地位较低的人携带特定的ET多态。DS大鼠的数据表明 与正常饮食的DS大鼠相比，高脂肪饮食可增强应激诱导的血压反应。 正常的脂肪饮食。鉴于儿童肥胖症的流行导致了高血压的风险，它是 对于确定导致增加的应激反应的机制很重要。低幼的童年 社会经济地位被认为与心血管疾病发病率和 死亡率。我们用已建立的大鼠早期生活应激模型开始了初步研究。小狗是 从出生第2天到第14天，每天与母亲分开3小时。早期生活应激(分离)大鼠表现出 与未分离的大鼠相比，它们对压力的反应更强。ET信号受损的大鼠 暴露在早期生活压力下的通路在成年后对压力没有增强的反应。 这些数据使我们预测，早期生活应激激活ET途径的一个组成部分，该成分 增强应激反应。我们提出了以下具体目标：具体目标1：测试 假设空气喷射应激激活ET和/或Ang II途径，从而刺激NADPH氧化酶 和/或解偶联一氧化氮合酶作为ROS的酶来源，使血压升高；具体目标2：测试 高脂饮食通过产生增加空气喷射应激引起的血压升高的假说 具体目标3：检验早期生活应激增强空气喷射应激诱导的假说 通过ET途径引起的血压升高。相关性：慢性应激源(高脂肪饮食和早期生活 压力)是已建立的压力源的模型，已知这种压力源会使人类对压力敏感，并增加 患高血压的风险。对血压反应机制的全面了解 压力可能会揭示将高血压风险降至最低的方法。

Project Summary: We have utilized an established model of behavioral stress in Dahl salt-sensitive (DS) rats that indicates reactive oxygen species (ROS) mediate the stress-induced increase in blood pressure. We have hypothesized that stress triggers ROS production via mechanisms involving the endothelin (ET) and/or angiotensin II pathways through activation of NADPH oxidase and uncoupled NOS. Project 2's BPStress Cohort of young adults has shown that the response to stress was significantly greater in obese individuals or ones at a lower socioeconomic status that carry a specific ET polymorphism. Data in DS rats indicates that a high fat diet augments the stress-induced blood pressure response when compared to DS rats on a normal fat diet. Given the epidemic of childhood obesity that has contributed to the risk of hypertension, it is important to determine the mechanisms responsible for the augmented stress response. Lower childhood socioeconomic status is recognized to be associated with increased cardiovascular disease morbidity and mortality. We initiated preliminary studies with an established model of early life stress in rats. Pups are separated from their mothers for 3 hr/day from day 2-14 of life. The early life stress (separated) rats display a greater response to stress when compared to the non-separated rats. Rats with an impaired ET signaling pathway that are exposed to early life stress do not have an augmented response to stress in adulthood. These data have led us to predict that early life stress activates a component of the ET pathway that potentiates the stress response. We propose the following specific aims: Specific Aim 1: To test the hypothesis that air jet stress activates the ET and/or Ang II pathways, which stimulates NADPH oxidase and/or uncoupled NOS as the enzymatic source of ROS, increasing blood pressure; Specific Aim 2: To test the hypothesis that high fat diet augments the air jet stress induced increase in blood pressure via production of ROS; Specific Aim 3: To test the hypothesis that early life stress potentiates the air jet stress induced increase in blood pressure via the ET pathway. Relevance: The chronic stressors (high fat diet and early life stress) are models of established stressors that are known to sensitize humans to stress and increase the risk for hypertension. A complete understanding of the mechanisms involved in the blood pressure response to stress may disclose approaches for minimizing the risk of hypertension.