Aldosterone and Diabetic Cardiovascular Disease: Research and Mentoring Progam

醛固酮和糖尿病心血管疾病：研究和指导计划

• 批准号: 8462676
• 负责人: Gail Kurr Adler
• 金额: $ 20.07万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-02 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462676
• 关键词: Acute; Address; Adenosine; Albuminuria; Aldosterone; Angiotensin II; Angiotensin II Receptor; Angiotensin-Converting Enzyme Inhibitors; Animals; Applications Grants; Area; Blood Pressure; Blood Vessels; Blood flow; Cardiac; Cardiovascular system; Chronic; Clinical Data; Clinical Investigator; Clinical Research; Coronary; Corticotropin; Data; Diabetes Mellitus; Double-Blind Method; Echocardiography; Educational process of instructing; Enalapril; Enzyme Inhibition; Functional disorder; Funding; Generations; Goals; Grant; Health; Heart; Heart Diseases; Heart failure; Hormones; Hydrochlorothiazide; Hypertension; Image; In Vitro; Individual; Inflammatory; Injury; Investigation; Kidney; Kidney Failure; Lead; Left; Mediator of activation protein; Mentors; Mineralocorticoid Receptor; Morbidity - disease rate; Mus; Myocardial; Myocardial perfusion; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Peptidyl-Dipeptidase A; Perfusion; Physicians; Placebos; Positron-Emission Tomography; Potassium; Randomized; Receptor Activation; Renal Circulation; Renal Plasma Flow; Renal function; Research; Research Personnel; Rest; Rodent; Role; Spironolactone; Stress; Stroke; Testing; Time; Tissues; Training; Training Support; Vascular Diseases; Ventricular; Work; cardiovascular injury; chemokine; cytokine; db/db mouse; diabetic; diabetic cardiomyopathy; effective therapy; eplerenone; heart circulation; heart function; improved; improved functioning; interest; kidney vascular structure; mortality; multidisciplinary; patient oriented; patient oriented research; pre-clinical; preclinical study; prospective; public health relevance; response; vascular inflammation; vasoactive agent

DESCRIPTION (provided by applicant): ABSTRACT This K24 application is to provide support for protected time for: 1) mentoring/teaching of junior clinical investigators; and 2) patient-oriented research investigating the role of aldosterone in the pathophysiology of diabetic cardiovascular disease. Recent data provide support for the hypothesis that activation of the mineralocorticoid receptor (MR) contributes to diabetic vascular injury, though the mechanisms are uncertain. Consistent with this hypothesis, our pre-clinical studies demonstrate that blockade of MR reduces renal injury in diabetic db/db mice and reduces vascular inflammation and cardiac and renal injury in hypertensive, angiotensin II (ANGII)-infused rodents. Our clinical studies show that short-term treatment with the MR antagonist eplerenone improves coronary circulatory function as compared to treatment with hydrochlorothiazide (HCTZ) in subjects with diabetes receiving angiotensin-converting enzyme (ACE) inhibition therapy. This observation could not be attributed to blood pressure changes suggesting that MR antagonists are not working via a classical renal effect, but via an additional, volume control-independent mechanism. This proposal tests the hypotheses that MR activation contributes to progression of vascular disease in subjects with type 2 diabetes mellitus (T2DM) receiving ACE inhibitor therapy, and consequently, MR antagonists exert beneficial effects by reducing vascular dysfunction and injury, inhibiting ANGII vascular effects, improving coronary circulatory and cardiac function and improving renovascular function. To address these hypotheses we will perform a prospective double-blind study in subjects with T2DM and hypertension receiving chronic ACE inhibitor therapy randomized to one of three treatments: 1) MR antagonist spironolactone; 2) HCTZ plus potassium; and 3) placebo. These studies provide a fertile area for investigation by trainees interested in patient-oriented research and will provide new information about the mechanisms by which MR antagonists reduce diabetic cardiovascular injury, with the goal of introducing new, effective treatments of cardiovascular injury in individuals with diabetes.

描述（由申请人提供）： 摘要 此 K24 申请旨在为以下方面的受保护时间提供支持： 1) 初级临床研究人员的指导/教学； 2）以患者为导向的研究，调查醛固酮在糖尿病心血管疾病病理生理学中的作用。最近的数据支持了盐皮质激素受体（MR）的激活导致糖尿病血管损伤的假设，尽管其机制尚不确定。与这一假设一致，我们的临床前研究表明，阻断 MR 可减少糖尿病 db/db 小鼠的肾损伤，并减少注射血管紧张素 II (ANGII) 的高血压啮齿动物的血管炎症以及心脏和肾脏损伤。我们的临床研究表明，对于接受血管紧张素转换酶 (ACE) 抑制治疗的糖尿病患者，与氢氯噻嗪 (HCTZ) 治疗相比，MR 拮抗剂依普利农 (eplerenone) 的短期治疗可改善冠状动脉循环功能。这一观察结果不能归因于血压变化，表明 MR 拮抗剂不是通过经典的肾脏效应发挥作用，而是通过一种额外的、与容量控制无关的机制发挥作用。该提案测试了以下假设：MR 激活有助于接受 ACE 抑制剂治疗的 2 型糖尿病 (T2DM) 受试者的血管疾病进展，因此 MR 拮抗剂通过减少血管功能障碍和损伤、抑制 ANGII 血管效应、改善冠状循环和心脏功能以及改善肾血管功能来发挥有益作用。为了解决这些假设，我们将对接受慢性 ACE 抑制剂治疗的 T2DM 和高血压受试者进行一项前瞻性双盲研究，随机接受以下三种治疗方法之一：1) MR 拮抗剂螺内酯； 2) HCTZ加钾； 3）安慰剂。这些研究为对以患者为导向的研究感兴趣的学员提供了一个广阔的研究领域，并将提供有关 MR 拮抗剂减少糖尿病心血管损伤机制的新​​信息，目标是为糖尿病患者引入新的、有效的心血管损伤治疗方法。