Hadoke Patrick W F, Iqbal Javaid, Walker Brian R
Centre for Cardiovascular Sciences, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
Br J Pharmacol. 2009 Mar;156(5):689-712. doi: 10.1111/j.1476-5381.2008.00047.x. Epub 2009 Feb 23.
The therapeutic potential for manipulation of glucocorticoid metabolism in cardiovascular disease was revolutionized by the recognition that access of glucocorticoids to their receptors is regulated in a tissue-specific manner by the isozymes of 11beta-hydroxysteroid dehydrogenase. Selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 have been shown recently to ameliorate cardiovascular risk factors and inhibit the development of atherosclerosis. This article addresses the possibility that inhibition of 11beta-hydroxsteroid dehydrogenase type 1 activity in cells of the cardiovascular system contributes to this beneficial action. The link between glucocorticoids and cardiovascular disease is complex as glucocorticoid excess is linked with increased cardiovascular events but glucocorticoid administration can reduce atherogenesis and restenosis in animal models. There is considerable evidence that glucocorticoids can interact directly with cells of the cardiovascular system to alter their function and structure and the inflammatory response to injury. These actions may be regulated by glucocorticoid and/or mineralocorticoid receptors but are also dependent on the 11beta-hydroxysteroid dehydrogenases which may be expressed in cardiac, vascular (endothelial, smooth muscle) and inflammatory (macrophages, neutrophils) cells. The activity of 11beta-hydroxysteroid dehydrogenases in these cells is dependent upon differentiation state, the action of pro-inflammaotory cytokines and the influence of endogenous inhibitors (oxysterols, bile acids). Further investigations are required to clarify the link between glucocorticoid excess and cardiovascular events and to determine the mechanism through which glucocorticoid treatment inhibits atherosclerosis/restenosis. This will provide greater insights into the potential benefit of selective 11beta-hydroxysteroid dehydrogenase inhibitors in treatment of cardiovascular disease.
认识到11β - 羟基类固醇脱氢酶的同工酶以组织特异性方式调节糖皮质激素与受体的结合后，心血管疾病中糖皮质激素代谢调控的治疗潜力发生了革命性变化。最近有研究表明，11β - 羟基类固醇脱氢酶1型的选择性抑制剂可改善心血管危险因素并抑制动脉粥样硬化的发展。本文探讨了在心血管系统细胞中抑制11β - 羟基类固醇脱氢酶1型活性是否有助于这种有益作用。糖皮质激素与心血管疾病之间的联系很复杂，因为糖皮质激素过量与心血管事件增加有关，但在动物模型中给予糖皮质激素可减少动脉粥样硬化和再狭窄。有大量证据表明，糖皮质激素可直接与心血管系统细胞相互作用，改变其功能、结构以及对损伤的炎症反应。这些作用可能受糖皮质激素和/或盐皮质激素受体调节，但也取决于可能在心脏、血管（内皮、平滑肌）和炎症（巨噬细胞、中性粒细胞）细胞中表达的11β - 羟基类固醇脱氢酶。这些细胞中11β - 羟基类固醇脱氢酶的活性取决于分化状态、促炎细胞因子的作用以及内源性抑制剂（氧甾醇、胆汁酸）的影响。需要进一步研究来阐明糖皮质激素过量与心血管事件之间的联系，并确定糖皮质激素治疗抑制动脉粥样硬化/再狭窄的机制。这将为选择性11β - 羟基类固醇脱氢酶抑制剂在治疗心血管疾病中的潜在益处提供更深入的见解。
