Aldosterone and Diabetic Cardiovascular Disease: Research and Mentoring Progam

摘要本K24申请旨在为以下方面提供保护时间支持：1)指导/教学初级临床研究者；2)以患者为研究对象，探讨醛固酮在糖尿病心血管疾病病理生理中的作用。最近的数据支持了矿化皮质激素受体（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，MR阻断可以减轻糖尿病db/db小鼠的肾损伤，并减少高血压、血管紧张素II （ANGII）输注的啮齿动物的血管炎症和心脏和肾脏损伤。我们的临床研究表明，在接受血管紧张素转换酶（ACE）抑制治疗的糖尿病患者中，与氢氯噻嗪（HCTZ）治疗相比，短期使用MR拮抗剂eplerenone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，这表明MR拮抗剂不是通过经典的肾脏效应起作用，而是通过另一种不依赖于体积控制的机制起作用。本研究验证了在接受ACE抑制剂治疗的2型糖尿病（T2DM）患者中MR激活有助于血管疾病进展的假设，因此MR拮抗剂通过减少血管功能障碍和损伤、抑制ANGII血管作用、改善冠状动脉循环和心脏功能以及改善肾血管功能发挥有益作用。为了验证这些假设，我们将在接受慢性ACE抑制剂治疗的T2DM和高血压患者中进行一项前瞻性双盲研究，随机分为三种治疗：1)MR拮抗剂螺内酯；2) HCTZ +钾；3)安慰剂。这些研究为对患者导向研究感兴趣的学员提供了一个肥沃的研究领域，并将提供关于MR拮抗剂减少糖尿病心血管损伤机制的新信息，目的是为糖尿病患者引入新的、有效的心血管损伤治疗方法。

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.