Cardiomyocyte Mineralocorticoid Receptors Are Essential for Deoxycorticosterone/Salt-Mediated Inflammation and Cardiac Fibrosis
Cardiomyocyte Mineralocorticoid Receptors Are Essential for Deoxycorticosterone/Salt-Mediated Inflammation and Cardiac Fibrosis
复制标题
DOI：
10.1161/hypertensionaha.112.203158
复制
发表时间：
2012-12-01
期刊：
影响因子：
8.3
通讯作者：
Young, Morag J.
中科院分区：
文献类型：
--
作者：
Rickard, Amanda J.;Morgan, James;Young, Morag J.
由于盐皮质激素受体在心脏重塑中的特定细胞类型中的作用仍然未知，我们比较了心肌细胞盐皮质激素受体缺失（MyoMRKO）和野生型（WT）小鼠在8天和8周时的心脏反应。未处理的WT和MyoMRKO小鼠之间的心脏功能没有差异，而基线时MyoMRKO心脏中的促纤维化标志物减少。在第8天，MyoMRKO显示单核细胞/巨噬细胞募集相当于WT小鼠对脱氧皮质酮/盐的反应，但与WT相比，纤维化标志物受到抑制。在8周时，MyoMRKO小鼠未显示脱氧皮质酮/盐诱导的炎性细胞浸润和胶原沉积或促炎基因表达增加。尽管两种基因型中的一些促纤维化标志物同等增加，但与WT相比，MyoMRKO小鼠还显示出转化生长因子-β/结缔组织生长因子抑制剂核心蛋白聚糖的mRNA和蛋白质基线水平增加，伴随着更高水平的基质金属蛋白酶2/基质金属蛋白酶9活性。这些数据表明心肌细胞盐皮质激素受体在脱氧皮质酮/盐诱导的组织炎症和重塑中的直接作用，并表明选择性盐皮质激素受体阻滞剂在心肌细胞中的心脏保护作用的潜在机制，可能涉及基质金属蛋白酶2/基质金属蛋白酶9活性和转化生长因子-β-结缔组织生长因子促纤维化途径的调节。（高血压。2012;60：1443-1450）。
Because the role of mineralocorticoid receptors in specific cell types in cardiac remodeling remains unknown, we have compared cardiac responses with deoxycorticosterone/salt in cardiomyocyte mineralocorticoid receptor-null (MyoMRKO) and wild-type (WT) mice at 8 days and 8 weeks. No differences in cardiac function between untreated WT and MyoMRKO mice were found, whereas profibrotic markers were reduced in MyoMRKO hearts at baseline. At 8 days, MyoMRKO showed monocyte/macrophage recruitment equivalent to WT mice in response to deoxycorticosterone/salt but a suppression of markers of fibrosis compared with WT. At 8 weeks, MyoMRKO mice showed no deoxycorticosterone/salt-induced increase in inflammatory cell infiltration and collagen deposition or in proinflammatory gene expression. Although some profibrotic markers were equivalently increased in both genotypes, MyoMRKO mice also showed increased baseline levels of mRNA and protein for the transforming growth factor-beta/connective tissue growth factor inhibitor decorin compared with WT that was accompanied by higher levels of matrix metalloproteinase 2/matrix metalloproteinase 9 activity. These data point to a direct role for cardiomyocyte mineralocorticoid receptor in both deoxycorticosterone/salt-induced tissue inflammation and remodeling and suggest potential mechanisms for the cardioprotective effects of selective mineralocorticoid receptor blockade in cardiomyocytes that may involve regulation of matrix metalloproteinase 2/matrix metalloproteinase 9 activity and the transforming growth factor-beta-connective tissue growth factor profibrotic pathway. (Hypertension. 2012;60:1443-1450.)