Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
Endocrinology. 2012 Nov;153(11):5346-60. doi: 10.1210/en.2012-1563. Epub 2012 Sep 18.
Glucocorticoids and their synthetic derivatives are known to alter cardiac function in vivo; however, the nature of these effects and whether glucocorticoids act directly on cardiomyocytes are poorly understood. To explore the role of glucocorticoid signaling in the heart, we used rat embryonic H9C2 cardiomyocytes and primary cardiomyocytes as model systems. Dexamethasone (100 nm) treatment of cardiomyocytes caused a significant increase in cell size and up-regulated the expression of cardiac hypertrophic markers, including atrial natriuretic factor, β-myosin heavy chain, and skeletal muscle α-actin. In contrast, serum deprivation and TNFα exposure triggered cardiomyocyte apoptosis, and these apoptotic effects were inhibited by dexamethasone. Both the hypertrophic and anti-apoptotic actions of glucocorticoids were abolished by the glucocorticoid receptor (GR) antagonist RU486 and by short hairpin RNA-mediated GR depletion. Blocking the activity of the mineralocorticoid receptor had no effect on these glucocorticoid-dependent cardiomyocyte responses. Aldosterone (1 μm) activation of GR also promoted cardiomyocyte hypertrophy and cell survival. To elucidate the mechanism of the dual glucocorticoid actions, a genome-wide microarray was performed on H9C2 cardiomyocytes treated with vehicle or dexamethasone in the absence or presence of serum. Serum dramatically influenced the transcriptome regulated by GR, revealing potential glucocorticoid signaling mediators in both cardiomyocyte hypertrophy and apoptosis. These studies reveal a direct and dynamic role for glucocorticoids and GR signaling in the modulation of cardiomyocyte function.
糖皮质激素及其合成衍生物已知可在体内改变心脏功能；然而，这些影响的性质以及糖皮质激素是否直接作用于心肌细胞仍知之甚少。为了探索糖皮质激素信号在心脏中的作用，我们使用大鼠胚胎 H9C2 心肌细胞和原代心肌细胞作为模型系统。地塞米松（100nm）处理心肌细胞可显著增加细胞大小，并上调心脏肥大标志物的表达，包括心钠素、β-肌球蛋白重链和骨骼肌α-肌动蛋白。相比之下，血清剥夺和 TNFα 暴露引发心肌细胞凋亡，而地塞米松抑制了这些凋亡作用。糖皮质激素的肥大和抗凋亡作用均被糖皮质激素受体（GR）拮抗剂 RU486 和短发夹 RNA 介导的 GR 耗竭所消除。阻断盐皮质激素受体的活性对这些糖皮质激素依赖性心肌细胞反应没有影响。醛固酮（1μm）激活 GR 也促进心肌细胞肥大和细胞存活。为了阐明糖皮质激素双重作用的机制，我们对用载体或地塞米松处理的 H9C2 心肌细胞进行了全基因组微阵列分析，其中血清或无血清存在。血清极大地影响了 GR 调节的转录组，揭示了心肌细胞肥大和凋亡中潜在的糖皮质激素信号转导介质。这些研究揭示了糖皮质激素和 GR 信号在调节心肌细胞功能中的直接和动态作用。
