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激素，与心血管疾病有关。最近，两项临床试验（RALES，EPHUSUS）表明，如果您通过给予药物阻止这种激素与介导其反应的受体结合来阻止这种激素的作用，则心力衰竭患者的健康状况会有所改善。醛固酮如何介导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，可以与醛固酮相同的受体结合。与醛固酮相反，糖皮质激素似乎在心脏中起基本的维持作用。我们的中心假设是，在健康的心脏中，醛固酮具有最小的影响，然而，在患病的心脏中，醛固酮相关的病理生理学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导中断的结果。这项拨款提案将解决醛固酮和糖皮质激素如何直接在心脏细胞内发出信号，以及这种信号在患病心脏中如何变化。此外，我们调查代谢糖皮质激素的酶，从而使他们非功能性的心脏疾病中发挥作用，如果我们可以逆转醛固酮的有害影响，通过人为增加糖皮质激素的生产在心脏。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，将有助于更好地了解醛固酮诱导的病理学，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.