Obesity, salt-sensitivity, and the natriuretic peptides

肥胖、盐敏感性和利钠肽

• 批准号: 8700469
• 负责人: Thomas J. Wang
• 金额: $ 57.67万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-05 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700469
• 关键词: Acute; Atrial Fibrillation; Behavioral; Biological Markers; Blood Plasma Volume; Blood Pressure; Body Weight decreased; Body mass index; Cardiac; Chronic; Clinical; Clinical Trials; Coronary heart disease; Development; Diet; Echocardiography; Enrollment; Excretory function; Heart; Heart failure; High Prevalence; Hormones; Hypertension; Individual; Infusion procedures; Kidney; Left Ventricular Mass; Measures; Mediator of activation protein; Morbidity - disease rate; Natriuretic Peptides; Obesity; Obesity Related Hypertension; Obesity associated cardiovascular disease; Organ; Physiological; Physiology; Prevention; Relative (related person); Renal Blood Flow; Renin-Angiotensin-Aldosterone System; Research; Research Personnel; Rest; Risk; Risk Factors; Role; Saline; Sodium; Sodium Chloride; Stimulus; Stress; Stroke; System; Testing; Therapeutic; Work; bariatric surgery; blood flow measurement; blood pressure regulation; cardiovascular risk factor; comparative; insight; modifiable risk; mortality; novel; novel strategies; post intervention; programs; response; salt balance; saluretic; urinary

DESCRIPTION (provided by applicant): One of the key mediators of cardiovascular risk in obesity is the development of hypertension. Obesity is the principal modifiable risk factor for hypertension, and one of the major contributors to its very high prevalence. Nonetheless, the mechanisms underlying the dysregulation of blood pressure in obesity are incompletely understood. An impaired ability to handle a salt load, or salt-sensitivity, is regarded as an important mechanism for obesity-related hypertension. Salt-sensitivity is determined by the balance of salt-retaining and salt-excreting systems. One of the best-studied salt-retaining systems is the renin-angiotensin-aldosterone system (RAAS). Excess RAAS activation in obesity is well-established. The principal counter-regulatory system to the RAAS is the natriuretic peptide (NP) system. The NPs are natriuretic and vasodilatory molecules produced by the heart in response to increased chamber stress. However, little is known regarding changes in the NP axis in obesity. In preliminary work, we have shown that obese individuals have decreased circulating NP concentrations, which reverse with weight loss. However, resting NP levels may not adequately reflect the ability of the NP axis to respond to stimuli, emphasizing the need for more detailed physiologic studies, under controlled salt conditions and with standardized assessment of the NP and RAAS axes, and related target organs (kidney, heart, and vasculature). We postulate that obesity promotes a state of relative "NP deficiency," which leads to impaired NP responses to salt loading, increased salt-sensitivity and elevated blood pressure. In Specific Aim 1, we will assess the NP and target organ responses to acute and chronic salt loading, in lean versus obese individuals. In Aim 2, we will examine the effect of weight loss on the NP and target organ responses to acute and chronic salt loading. The proposed research represents a systematic effort to build upon the investigators' prior clinical investigations into the novel interactions between the NP axis, obesity, and cardiometabolic risk. These studies have the potential to provide important insight into the causes of hypertension in obesity. Furthermore, because the NP system is easily accessible to pharmacologic manipulation, establishing that "NP deficiency" exists and defining its physiologic consequences could suggest novel approaches to the treatment and prevention of obesity-related cardiovascular disease.

描述（由申请人提供）：肥胖者心血管风险的关键调节因素之一是高血压的发生。肥胖是高血压的主要可改变危险因素，也是其患病率极高的主要原因之一。尽管如此，肥胖引起的血压失调的机制尚不完全清楚。处理盐负荷或盐敏感性的能力受损被认为是肥胖相关高血压的重要机制。盐敏感性由持盐系统和排盐系统的平衡决定。研究最透彻的保盐系统之一是肾素-血管紧张素-醛固酮系统（RAAS）。肥胖症中 RAAS 过度激活已被证实。 RAAS 的主要反监管系统是利尿钠肽 (NP) 系统。 NP 是心脏响应增加的心室压力而产生的利尿钠和血管舒张分子。然而，对于肥胖中 NP 轴的变化知之甚少。在初步工作中，我们已经表明，肥胖个体的循环 NP 浓度降低，这种情况随着体重减轻而逆转。然而，静息 NP 水平可能不足以反映 NP 轴对刺激作出反应的能力，强调需要在受控盐条件下以及对 NP 和 RAAS 轴以及相关靶器官（肾、心脏和脉管系统）进行标准化评估进行更详细的生理学研究。我们假设肥胖会促进相对“NP 缺乏”的状态，从而导致 NP 对盐负荷的反应受损、盐敏感性增加和血压升高。在具体目标 1 中，我们将评估瘦个体与肥胖个体对急性和慢性盐负荷的 NP 和靶器官反应。在目标 2 中，我们将研究减肥对 NP 和靶器官对急性和慢性盐负荷反应的影响。拟议的研究代表了一项系统性的努力，以研究人员之前对 NP 轴、肥胖和心脏代谢风险之间的新相互作用进行的临床研究为基础。这些研究有可能为肥胖导致高血压的原因提供重要的见解。此外，由于 NP 系统很容易进行药物操作，因此确定“NP 缺乏”的存在并定义其生理后果可能会提出治疗和预防肥胖相关心血管疾病的新方法。

项目成果

Natriuretic Peptides and Cardiometabolic Health.

• DOI: 10.1253/circj.cj-15-0589
• 发表时间: 2015
• 期刊: Circulation journal : official journal of the Japanese Circulation Society
• 作者: Gupta DK;Wang TJ
• 通讯作者: Wang TJ

Regulation of B-type natriuretic peptide synthesis by insulin in obesity in male mice.

胰岛素对肥胖雄性小鼠 B 型利尿钠肽合成的调节。

• DOI: 10.1113/ep085091
• 发表时间: 2016
• 期刊: Experimental physiology
• 影响因子: 2.7
• 作者: Zhang,Haihua;Thoonen,Robrecht;Yao,Vincent;Buys,EmmanuelS;Popovich,John;Su,YanRu;Wang,ThomasJ;Scherrer-Crosbie,Marielle
• 通讯作者: Scherrer-Crosbie,Marielle

Racial Differences in Natriuretic Peptide Levels: The Dallas Heart Study.

• DOI: 10.1016/j.jchf.2015.02.008
• 发表时间: 2015-07
• 期刊: JACC-HEART FAILURE
• 影响因子: 13
• 作者: Gupta, Deepak K.;de Lemos, James A.;Ayers, Colby R.;Berry, Jarett D.;Wang, Thomas J.
• 通讯作者: Wang, Thomas J.