Role of gut commensal Coprococcus comes in angiotensin-converting enzyme inhibitor resistant hypertension

项目摘要和摘要 在美国，高血压是一个严重的公共卫生问题。难治性高血压的定义是 对至少三类降压药的治疗反应差的高血压，其中一种 这是利尿剂。尽管有多种抗高血压药物可用，但约20%的 高血压患者属于顽固性高血压。肠道微生物区系是一个紧急而重要的参与者 在高血压的发生和发展中起重要作用。最近，肠道微生物群被证明与药物有关。 新陈代谢，然后影响它们的效率。在体外和体内，我们的实验室发现肠道 共生球菌能分解血管紧张素转换酶(ACE)抑制物 奎那普利。根据顽固性高血压的临床表型和我们的初步数据，我们建议 研究C在血管紧张素转换酶抑制剂代谢和血管紧张素转换酶的发展中的作用 高血压。中心假设是C.Come通过两种途径导致ACE抑制剂抵抗性高血压 独立机制：(1)能分解ACE抑制剂，降低其降压作用； (2)能使宿主血压升高。这项研究的具体目的是调查这两个独立的 机制：(1)确定假单胞菌是否能分解ACE抑制剂；(2)确定假单胞菌是否能 使宿主血压升高。为了实现这些目标，我们将进行体外实验，以量化 最常用的血管紧张素转换酶抑制剂的分解代谢。血管紧张素转换酶抑制剂的降压作用 将利用高血压大鼠模型在体内进行研究，无论是否存在C.Come。实验： 用或不用C.Comes治疗的正常血压和高血压大鼠将被用来说明 C.的参与涉及血压调节。这个项目的长期目标是揭示一个 新的机制，通过来促进顽固性高血压。因此，特定的肠道微生物区系或 肠道共生菌的改变将使高血压人群受益，尤其是抵抗力 高血压患者。顽固性高血压背后的机制尚不清楚。因此，常见的 难治性高血压患者控制血压的方法只是徒劳地添加或替代 药物。鉴于这些事实，这个项目具有很大的科学和临床意义，因为 肠道共生C在难治性高血压病因学中的机制作用将导致潜在 难治性高血压的管理和治疗策略。美国国家心肺血液研究所 已经公布了工作组的几份报告，强调对肠道微生物区系、性 差异和翻译障碍。目前的提议符合这些报告和特派团 美国国家卫生研究院的。

Project summary and abstract In the United States, hypertension is a serious public health concern. Resistant hypertension is defined as hypertension with poor responses to the treatment of at least three classes of antihypertensive drugs, one of which is diuretic. Despite the availability of multiple classes of antihypertensive drugs, approximately 20% of hypertensive patients belong to resistant hypertension. Gut microbiota is an emergent and important participant in the initiation and progression of hypertension. Recently, the gut microbiota is shown to be involved in drug metabolism and thereafter impacts their efficacies. In vitro and in vivo, our lab has discovered that the gut commensal Coprococcus comes is capable of catabolizing the angiotensin-converting enzyme (ACE) inhibitor quinapril. Based on clinical phenotypes of resistant hypertension and our preliminary data, we propose to investigate the functions of C. comes in the metabolism of ACE inhibitors as well as in the development of hypertension. The central hypothesis is that C. comes leads to ACE inhibitor resistant hypertension via two independent mechanisms: (1) it can catabolize ACE inhibitors and reduce their blood pressure-lowering effects; and (2) it can raise host blood pressure. The specific aims of this study are to investigate the two independent mechanisms: (1) determine if C. comes can catabolize ACE inhibitors; and (2) determine if C. comes can increase host blood pressure. To execute these aims, we will conduct in vitro experiments to quantify the catabolism of the most widely prescribed ACE inhibiors. The blood pressure-lowering effect of ACE inhibitors will be studied in vivo utilizing hypertensive rat models, whether or not C. comes is present. Experiments on normotensive and hypertensive rats treated with or without C. comes will be conducted to illustrate the involvement of C. comes in blood pressure regulation. The long-term objective of this project is to uncover a novel mechanism by which C. comes contributes to resistant hypertension. Therefore, specific gut microbiota or gut commensal C. comes alterations would benefit the hypertensive population, particularly resistant hypertensive patients. The mechanisms behind resistant hypertension remains unclear. Thus, the common approach to blood pressure control in resistant hypertension is simply the futile addition or substitution of medications. Given these facts, this project is of great scientific and clinical relevances, since the demonstrating the mechanistic role of gut commensal C. comes in the etiology of resistant hypertension will lead to potential strategies for resistant hypertension management and therapy. The National Heart, Lung, and Blood Institute has announced several reports from working groups to emphasize the research on gut microbiota, sex differences, and translational barriers. The current proposal is in accordance with these reports and the mission of the National Institute of Health.