ALDOSTERONE--A CARDIOVASCULAR RISK FACTOR

描述：(改编自《调查者摘要》)在过去的十年里， 人们对醛固酮作为心血管疾病的致病激素的兴趣 发生了。除了众所周知的对血压和钠的影响 (Na+)、K+(K+)和H+(H+)动态平衡，与醛固酮有关 伴有心肌肥大、纤维化、肾病和中风。其中一些 增强纤溶酶原释放的作用可能是次要的。 激活物抑制物，1型(PAI-1)。因此，醛固酮分泌紊乱 可能是心血管损害和高血压之间的重要联系 心力衰竭。血管紧张素II(AngII)有几种类似于 醛固酮。由于血管紧张素转换酶还调节醛固酮的分泌，这种相互作用 这两个潜在的心血管危险因素中的一个需要澄清。这个 这项提议的总体目标是检验如下假设：醛固酮是一种 心血管风险荷尔蒙。这些研究的结果将与 几种人类疾病，例如充血性心力衰竭，肾功能衰竭， 动脉粥样硬化和高血压。为了实现这一总体目标，他们将 提出三组具体目标。首先，他们将确立原则 这种醛固酮会导致心血管损伤，并确定其程度。他们会 使用三种大鼠模型：1)血管紧张素转换酶抑制剂和钠离子对一氧化氮合酶的抑制 补充，2)单肾切除加醛固酮和Na+补充， (3)单肾切除加补充血管紧张素和钠离子。初步数据 记录所有三种模型都会导致心血管损害，以及醛固酮 是一个可能的调解人。其次，他们将定义一些潜在的 机械装置。将使用两种方法：1)它们将确定 诱发心血管损害所需的Na+摄入量，评估是否增加K+ 摄入相当于阻断了醛固酮抑制损伤的作用， 并确定暴露于必要的实验范式的持续时间 造成损害。2)他们将评估中介机构的作用，包括 组织血管紧张素Ⅱ、纤溶酶原激活物-1、转化生长因子-β1、胶原合成、 用细胞和分子技术进行Na+，H+交换和Na+，K+ATPase， 包括鼠标击倒模型。第三，他们将决定是否 已建立的心血管损伤可以通过修改醛固酮来逆转 行动。他们的结果应该更好地定义使用 盐皮质激素拮抗剂在预防心脏损害中的作用 当醛固酮水平不适当地升高时，肾脏和其他组织 与Na+摄入量水平相关。

DESCRIPTION: (Adapted from the Investigator's Abstract) Over the past decade, interest in aldosterone as a pathogenic hormone in cardiovascular disease has occurred. In addition to its well-known effect on blood pressure and on sodium (Na+), potassium (K+) and hydrogen (H+) homeostasis, aldosterone is associated with cardiac hypertrophy, fibrosis, nephropathy and strokes. Some of these effects may be secondary to potentiation of the release of plasminogen activator inhibitor, type 1 (PAI-1). Thus, derangement in aldosterone secretion may be an important link between cardiovascular damage and hypertension and heart failure. Angiotensin II (AngII) has several effects similar to aldosterone. Since AngII also regulates aldosterone secretion, the interaction of these two potential cardiovascular risk factors needs to be clarified. The overall goal of this proposal is to test the hypothesis that aldosterone is a cardiovascular risk hormone. The results of these studies will be relevant for several human disease, e.g., congestive heart failure, renal failure, atherosclerosis, and hypertension. To accomplish this overall goal, they will address three groups of specific aims. First, they will establish the principle that aldosterone induces cardiovascular damage and define its extent. They will use three rat models: 1) nitric oxide synthase inhibition with AngII and Na+ supplementation, 2) uninephrectomy with aldosterone and Na+ supplementation, and 3) uninephrectomy with AngII and Na+ supplementation. Preliminary data document that all three models induced cardiovascular damage, and aldosterone is a likely mediator. Second, they will define some of the underlying mechanisms. Two approaches will be used: 1) they will determine the level of Na+ intake required to induce cardiovascular damage, assess if increasing K+ intake is equivalent to blocking aldosterone's effect in inhibiting the damage, and determine the duration of exposure to the experimental paradigm necessary to produce damage. 2) they will assess the role of intermediaries, including tissue AngII, PAI-1, transforming growth factor-beta 1, collagen synthesis, Na+, H+ exchange and Na+, K+ ATPase using cellular and molecular techniques, including mouse knock-out models. Third, they will determine whether established cardiovascular damage can be reversed by modifying aldosterone's action. Their results should better define the rationale for the use of mineralocorticoid antagonists in the prophylaxis of damage to the heart, the kidney and other tissues when aldosterone levels are inappropriately elevated relative to the level of Na+ intake.