MECHANISMS OF ALDO-INDUCED MYOCARDIAL FIBROSIS (TREATMENT)

ALDO 诱发心肌纤维化的机制（治疗）

• 批准号: 7603251
• 负责人: DAVID A CALHOUN
• 金额: $ 1.58万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603251
• 关键词: Adrenal Cortex Hormones; Aldosterone; Attenuated; Blood Pressure; Cardiac; Chronic; Chymosin; Computer Retrieval of Information on Scientific Projects Database; Experimental Models; Fibrosis; Funding; Genetic Models; Grant; Heart; Heart Hypertrophy; Human; Hyperaldosteronism; Hypertension; Hypertrophy; Inflammation; Inflammatory; Ingestion; Institution; Left Ventricular Hypertrophy; Left Ventricular Remodeling; Minerals; Myocardial; Oxidative Stress; Pathway interactions; Patients; Process; Relative (related person); Research; Research Personnel; Resistance; Resources; Role; Sodium Chloride; Sodium-Restricted Diet; Source; Spironolactone; System; Testing; Thinking; Time; United States National Institutes of Health; cardiovascular risk factor; receptor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Studies in humans have indicated that aldosterone excess induces left ventricular (LV) hypertrophy independent of hypertension. Ultrasonographic studies further suggest myocardial hypertrophy due to hyperaldosteronism occurs concomitantly with myocardial fibrosis. The importance of these findings is highlighted by our resent observation that primary aldosteronism (PA) is several times more prevalent in patients with resistant hypertension than previously thought. Interestingly, in patients with resistant hypertension, chronic blockade of the rennin-angiotensis system (RAS) does not attenuate LV hypertrophy in PA patients relative to non-PA patients despite a similar blood pressure reduction. The central role of aldosterone in promoting perivascular inflammation and fibrosis in the heart independent of blood pressure has been confirmed in experimental models of hyperaldosteronism. The pro-fibrotic action is blocked not only by mineral corticoid receptor antagonism but also by a low-salt diet. This important observation as well as the general relation between NaC1 and aldosterone to LV remodeling remains to be elucidated m humans. We hypothesize that adosterone-induced myocardial fibrosis is primarily an inflammatory process that depends highly on the dietary salt status. To test this hypothesis we will: Specific Aim 1) To show that in humans, aldosterone excess causes LV hypertrophy and fibrosis through inflammatory pathways, we will relate markers of inflammation and oxidative stress to LV hypertrophy and fibrosis in PA patients; Specific Aim 2 ) We expect that spironolactone will reverse cardiac hypertrophy in PA patients. However, in this aim, we will examine if spironolactone -dependentent reverse-LV remodeling relates to markers of inflammation and/or cardiac fibrosis in these patients; Specific Aim 3) Show that salt restriction reduces myocardial fibrosis , inflammation, and oxidative stress in patients with PA; Specific Aim 4) Using genetic models and pharmacologic approaches, show a cause-and-effect relation between aldosterone-induced inflammation and subsequent cardiac fibrosis. If these proposed studies show that inappropriately high aldosterone secretion relative to dietary salt ingestion causes adverse cardiac remodeling, a new paradigm would be created in which the "aldosterone-salt product" predicts cardiovascular risk.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 在人类中的研究表明，醛固酮过量诱导左心室（LV）肥大无关高血压。 超声检查进一步表明，由于心肌纤维化同时发生的心肌肥大。 这些发现的重要性是通过我们的怨恨观察到的，即在耐药性高血压患者中，原发性醛固酮主义（PA）比以前想象的要高出几倍。有趣的是，在具有耐药性高血压的患者中，尽管血压降低相似，但相对于非PA患者，肾素 - 血管紧张系统（RAS）的慢性阻断不会减弱PA患者的LV肥大。醛固酮在促进血管周围的炎症和纤维化中与血压无关的纤维化中的核心作用已在大甲醛酸实验模型中得到证实。促纤维化作用不仅被矿物质皮质受体拮抗作用阻止，而且还通过低盐饮食阻止。这种重要的观察结果以及NAC1与醛固酮与LV重塑之间的一般关系尚待阐明。我们假设脂肪酮诱导的心肌纤维化主要是炎症过程，高度取决于饮食盐状态。 为了检验这一假设，我们将：特定目的1）表明，在人类中，醛固酮过量会通过炎症途径引起LV肥大和纤维化，我们将将炎症和氧化应激的标志物与PA患者的LV肥大和纤维化联系起来； 具体目标2）我们预计螺内酯会逆转PA患者的心脏肥大。 但是，在此目标中，我们将检查螺内酯依赖性反向LV重塑是否与这些患者的炎症和/或心脏纤维化标记有关； 具体目的3）表明盐限制PA患者的心肌纤维化，炎症和氧化应激； 特定目的4）使用遗传模型和药理方法，显示醛固酮诱导的炎症与随后的心脏纤维化之间的因果关系。如果这些提出的研究表明，相对于饮食摄入摄入的醛固酮分泌不当会导致心脏重塑，则将创建一个新的范式，其中“醛固酮 - 盐产物”预测心血管风险。