Autonomic: Angiotensin-(1-7) Interactions in Hypertension

高血压是一个主要的公共卫生问题，与心脏病和中风的风险增加有关，是世界范围内死亡的主要原因。大多数高血压患者现在肥胖，许多人患有胰岛素抵抗，但与心血管和代谢紊乱有关的分子机制在这种疾病中尚不完全清楚。越来越多的证据表明，肾素-血管紧张素系统（RAS），特别是血管紧张素（Ang） II的过度活性，在高血压和胰岛素抵抗中起致病作用，部分是通过调节交感神经系统。最近，血管舒张肽Ang-(1-7)，其对抗Ang II的作用，被认为与高血压的发病机制有关。虽然Ang-(1-7)在啮齿类动物中降低血压并改善胰岛素作用，但这些作用的确切机制尚不清楚。此外，人类的研究有限且相互矛盾，我们认为这是由于自主缓冲机制抑制了Ang-(1-7)心血管作用。我们还提出Ang-(1-7)通过抑制交感神经系统改善心血管和代谢功能。事实上，我们的初步数据表明，在临床人群中，交感神经激活的血浆Ang-(1-7)水平降低。此外，这种Ang-(1-7)缺乏似乎与交感神经系统相互作用，导致高血压和胰岛素抵抗。基于这些发现，我们将检验Ang-(1-7)通过对抗交感神经系统降低血压和改善胰岛素敏感性的整体假设。我们将采用一种创新的转化方法，在动物和人类实验模型中结合综合生理学和药理学方法来检验这一假设。在Aim 1中，我们将利用中枢和外周自主神经衰竭患者的独特特征来确定在没有压力反射缓冲的情况下，交感神经溶解和外周血管扩张机制分别对Ang-(1-7)效应的贡献。在Aim 2中，我们将研究Ang-(1-7)对果糖喂养大鼠（已建立的心脏代谢综合征动物模型）外周和肝脏胰岛素敏感性的影响，以及这些影响是否涉及交感神经抑制。最后，在独立阶段，PI将研究内源性Ang-(1-7)：交感神经相互作用对果糖喂养大鼠心血管和代谢功能的重要性。这些集体研究将完成pi的短期研究目标，即检查交感神经系统和Ang-(1-7)之间在心血管和代谢调节中的相互作用。这些研究的发现将提高我们对RAS的机制通路的理解，并有可能推进当前高血压领域的概念，以改善这种疾病的靶向治疗方法和结果。这些研究在逻辑上建立在PI在心血管自主调节方面的翻译背景之上，并将为建立一个独立和新颖的研究领域提供强大的培训和研究框架。PI将获得新的专业知识和技能，在这个应用程序的指导阶段评估啮齿动物胰岛素作用的前沿方法，以补充她的综合动物和临床心血管训练，并为成为一名精英研究者提供基础

DESCRIPTION (provided by applicant): Project Summary Hypertension is a major public health problem associated with an increased risk for heart disease and stroke, leading causes of death worldwide. The majority of hypertensive subjects are now obese and many suffer from insulin resistance, but the molecular mechanisms linking cardiovascular and metabolic derangements in this disease are not fully understood. Increasing evidence suggests that the renin-angiotensin system (RAS), in particular overactivity of angiotensin (Ang) II, plays a pathogenic role in both hypertension and insulin resistance in part through modulation of the sympathetic nervous system. More recently, the vasodilatory peptide Ang-(1-7), which opposes Ang II actions, has been implicated in the pathogenesis of hypertension. While Ang-(1-7) lowers blood pressure and improve insulin action in rodents, the precise mechanisms involved in these effects are unclear. In addition, there are limited and contradictory studies in humans, and we propose that this is due to restraint of Ang-(1-7) cardiovascular actions by autonomic buffering mechanisms. We also propose that Ang-(1-7) improves cardiovascular and metabolic function by inhibiting the sympathetic nervous system. Indeed, our preliminary data suggests that plasma Ang-(1-7) levels are reduced in clinical populations with sympathetic activation. Furthermore, this Ang-(1-7) deficiency appears to interact with the sympathetic nervous system to contribute to hypertension and insulin resistance. Based on these findings, we will test the overall hypothesis that Ang-(1-7) lowers blood pressure and improves insulin sensitivity by opposing the sympathetic nervous system. We will use an innovative translational approach to test this hypothesis that combines integrative physiologic and pharmacologic methods in animal and human experimental models. In Aim 1, we will take advantage of the unique characteristics of central and peripheral autonomic failure patients to determine the contribution of sympatholytic and peripheral vasodilatory mechanisms, respectively, to Ang-(1-7) effects in the absence of baroreflex buffering. In Aim 2, we will examine Ang-(1-7) effects on peripheral and hepatic insulin sensitivity in fructose-fed rats, an established animal model of cardio-metabolic syndrome, and whether these effects involve sympathetic inhibition. Finally, in the independent phase, the PI will examine the importance of endogenous Ang-(1-7): sympathetic interactions to cardiovascular and metabolic function in fructose-fed rats. These collective studies will accomplish the PIs short-term research objective to examine interactions between the sympathetic nervous system and Ang-(1-7) for cardiovascular and metabolic regulation. The findings from these studies will improve our understanding of mechanistic pathways of the RAS, and have the potential to advance current concepts in the field of hypertension to improve targeted treatment approaches and outcomes in this disease. These studies logically build upon the PI's translational background in cardiovascular autonomic regulation, and will provide strong training and a research framework to establish an independent and novel area of research. The PI will acquire new expertise and skills in cutting edge methods to assess insulin action in rodents in the mentored phase of this application, to complement her integrative animal and clinical cardiovascular training and to provide the foundation to be an elite investigator with the capabilities to comprehensively investigate cardio-metabolic function. The clinical studies will be performed under the mentorship of Dr. Italo Biaggioni at Vanderbilt University, a world renowned physician scientist with expertise in neural-metabolic interactions, and in autonomic disorders including primary autonomic failure. The PI will receive training in hyperinsulinemic-euglycemic clamps under the co-mentor Dr. David Wasserman, an expert in metabolism with over 20 years of experience in these methods. The PI has also established an outstanding mentoring team with a proven track record of mentorship and scientific expertise in the RAS, experimental and clinical hypertension, autonomic neuroscience, and biostatistics. Thus, these studies will be conducted in the optimal scientific environment with input from highly experienced mentors, access to unique patient populations, state-of-the-art clinical research and animal facilities, and a wealth of institutional resources for career development. Finally, the PI will participate in extramural activities to enhance her progression into an independent investigator including continued service on national physiology, pharmacology and autonomic committees, reviewing for journals and participating in teaching and mentorship opportunities. Overall, this proposal will advance the PIs long-term research and career goals, to establish a translational independent research program focused on the neural mechanisms of hypertension.