Aldosterone mediated cardiac pathophysiology:The role of corticosteroid receptors and 11 HSD isoforms

醛固酮是一种在血液中循环的荷尔蒙，与心血管疾病有关。最近，两项临床试验(rales，EPHUSUS)表明，如果你通过给予抑制这种荷尔蒙与介导其反应的受体结合的药物来阻止这种荷尔蒙的作用，心力衰竭患者的健康就会得到改善。醛固酮如何调节其对心脏的有害影响在很大程度上是未知的。糖皮质激素是另一种在血液中循环的激素，可以与醛固酮结合在同一受体上。与醛固酮相反，糖皮质激素似乎在心脏中起着基本的维持作用。我们的中心假设是，在健康的心脏中，醛固酮的影响微乎其微，然而，在患病的心脏中，与醛固酮相关的病理生理是醛固酮向细胞发出信号的能力增加和糖皮质激素信号传递中断的结果。这项拨款提案将解决醛固酮和糖皮质激素如何在心肌细胞内直接发出信号，以及这种信号如何在患病心脏中发生变化。此外，我们还调查了代谢糖皮质激素从而使其失去功能的酶是否在心脏病中发挥作用，以及我们是否可以通过人为增加心脏中糖皮质激素的产生来逆转醛固酮的有害影响。通过了解醛固酮促进心脏疾病的机制，以及糖皮质激素及其代谢在这一过程中的作用，将有助于更好地理解醛固酮诱导的病理，从而导致新的治疗靶点。

Aldosterone a hormone that circulates in blood and is associated with cardiovascular disease. Recently, two clinical trials (RALES, EPHUSUS) demonstrate that if you stop this hormone from acting by giving drugs that inhibit it from binding to the receptor that mediates its response, there is an improvement in the health of heart failure patients. How aldosterone mediates its detrimental effects on heart is largely unknown. Glucocorticoids are another hormone that circulates in blood and can bind to the same receptor as aldosterone. In contrast to aldosterone glucocorticoids appear to play a basic maintenance role in heart. Our central hypothesis is that in the healthy heart aldosterone has minimal effects , however, in the diseased heart aldosterone associated pathophysiology is a result of both an increase in the ability of aldosterone to signal to cells and disruption of glucocorticoid signalling. This grant proposal will address how aldosterone and glucocorticoids may directly signal within cardiac cells and how this signalling changes in the diseased heart. In addition, we investigate if enzymes that metabolize glucocortioids and thus render them non-functional play a role in cardiac disease, and if we can reverse the detrimental effects of aldosterone by artificially increasing the production of glucocorticoids in heart. By understanding the mechanisms by which aldosterone promotes cardiac disease, and the role of glucocorticoids and their metabolism in this process will lead to a better understanding of aldosterone induced pathology and thus lead to novel therapeutic targets.