Łabuzek Krzysztof, Liber Sebastian, Bułdak Łukasz, Krupej-Kędzierska Joanna, Machnik Grzegorz, Bobrzyk Magdalena, Okopień Bogusław
Eur J Pharmacol. 2014 Mar 5;726:96-108. doi: 10.1016/j.ejphar.2014.01.043.
Alternative activation of macrophages plays protective role in cardiac remodelling in heart failure and the activity of mineralocorticoid receptor may determine the phenotype of these cells. We examined the influence of eplerenone, aldosterone, and IL-4 on descriptors of alternative activation in blood monocytes collected from 19 patients with heart-failure and 20 healthy volunteers. “Heart failure” macrophages in comparison with “healthy” macrophages had increased mineralocorticoid activity, NO and reactive oxygen species production, expression of iNOS mRNA and protein, but decreased expression of arginase I and mannose receptor proteins, and activity of MnSOD and CuZnSOD. Aldosterone increased mineralocorticoid activity, NO and reactive oxygen species production, iNOS mRNA and protein expression, MnSOD and CuZnSOD activity. Eplerenone attenuated the effects of aldosterone on all but MnSOD and CuZnSOD variables. Eplerenone alone increased the production of NO, MnSOD and CuZnSOD activity, arginase I gene and protein expression, and mannose receptor gene and protein expression, but decreased mineralocorticoid activity only in “heart failure” macrophages. The latter suggests altered function of mineralocorticoid receptor in heart failure. Increased mineralocorticoid activity accounts for increased NO production, iNOS gene and protein expression but does not explain the increased basal reactive oxygen species production and decreased markers of alternative activation in “heart failure” macrophages. In the lack of change in basal mineralocorticoid activity, eplerenone increases markers of alternative activation in a mineralocorticoid receptor-independent manner. Because of changes in iNOS and NO variable, eplerenone induced qualitatively different activation of macrophages from that obtained with IL-4.
巨噬细胞的替代性激活在心力衰竭的心脏重塑中发挥保护作用，而盐皮质激素受体的活性可能决定这些细胞的表型。我们研究了依普利酮、醛固酮和白细胞介素-4对从19例心力衰竭患者和20名健康志愿者采集的血液单核细胞中替代性激活指标的影响。与“健康”巨噬细胞相比，“心力衰竭”巨噬细胞的盐皮质激素活性、一氧化氮（NO）和活性氧生成增加，诱导型一氧化氮合酶（iNOS）mRNA和蛋白表达增加，但精氨酸酶I和甘露糖受体蛋白表达降低，锰超氧化物歧化酶（MnSOD）和铜锌超氧化物歧化酶（CuZnSOD）活性降低。醛固酮增加盐皮质激素活性、NO和活性氧生成、iNOS mRNA和蛋白表达、MnSOD和CuZnSOD活性。依普利酮减弱了醛固酮对除MnSOD和CuZnSOD变量外所有指标的影响。单独使用依普利酮增加了NO生成、MnSOD和CuZnSOD活性、精氨酸酶I基因和蛋白表达以及甘露糖受体基因和蛋白表达，但仅在“心力衰竭”巨噬细胞中降低了盐皮质激素活性。后者提示心力衰竭中盐皮质激素受体功能改变。盐皮质激素活性增加导致NO生成增加、iNOS基因和蛋白表达增加，但不能解释“心力衰竭”巨噬细胞中基础活性氧生成增加和替代性激活标志物减少的现象。在基础盐皮质激素活性无变化的情况下，依普利酮以不依赖盐皮质激素受体的方式增加替代性激活标志物。由于iNOS和NO变量的变化，依普利酮诱导的巨噬细胞激活在性质上不同于白细胞介素-4诱导的激活。
