Pressure overload inhibits glucocorticoid receptor transcriptional activity in cardiomyocytes and promotes pathological cardiac hypertrophy
Pressure overload inhibits glucocorticoid receptor transcriptional activity in cardiomyocytes and promotes pathological cardiac hypertrophy
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压力超负荷抑制心肌细胞糖皮质激素受体转录活性并促进病理性心脏肥大
DOI：
10.1016/j.yjmcc.2019.03.019
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发表时间：
2019
影响因子：
5
通讯作者：
Sano Motoaki
中科院分区：
文献类型：
--
作者：
Matsuhashi Tomohiro;Endo Jin;Katsumata Yoshinori;Yamamoto Tsunehisa;Shimizu Noriaki;Yoshikawa Noritada;Kataoka Masaharu;Isobe Sarasa;Moriyama Hidenori;Goto Shinichi;Fukuda Keiichi;Tanaka Hirotoshi;Sano Motoaki
糖皮质激素受体（GR）在心肌细胞中大量表达。然而，GR在调节压力超负荷引起的心肌肥厚和心力衰竭中的作用尚不清楚。使用Cre-lox系统产生心肌细胞特异性GR敲除（GRcKO）小鼠、盐皮质激素受体（MR）敲除（MRcKO）小鼠以及GR和MR双KO（GRMRdcKO）小鼠。与对照组（GRf/f）小鼠相比，GRcKO小鼠对压力超负荷的反应表现出更差的心脏重塑，包括心脏重量与体重比的更大增加，心肌细胞大小的更大增加，左心室收缩力的更大下降以及胎儿基因的更高再激活。MRcKO小鼠显示与对照（MRf/f）小鼠相比相当程度的心脏重构。压力超负荷GRcKO小鼠中更差的心脏重塑不是由于心肌细胞MR的代偿性激活，因为压力超负荷GRMRdcKO小鼠显示与GRcKO小鼠相同程度的心脏重塑。压力超负荷抑制心脏GR靶基因表达。虽然血浆皮质酮水平和GR（核/胞质GR）的亚细胞定位没有改变，染色质免疫沉淀试验显示，GR募集到GR-靶基因的启动子显着抑制压力过载。在压力超负荷心脏中，将GR靶基因的表达恢复到与假手术心脏相同的程度，可减弱不良心脏重塑。因此，GR在压力超负荷时作为不良心脏重塑的抑制物起作用，但GR介导的转录在压力超负荷下被抑制。在压力超负荷下维持心肌细胞中GR介导的转录的疗法可能是心力衰竭的有希望的治疗策略。
Glucocorticoid receptor (GR) is abundantly expressed in cardiomyocytes. However, the role of GR in regulating cardiac hypertrophy and heart failure in response to pressure overload remains unclear. Cardiomyocyte-specific GR knockout (GRcKO) mice, mineralocorticoid receptor (MR) knockout (MRcKO), and GR and MR double KO (GRMRdcKO) mice were generated using the Cre-lox system. In response to pressure overload, GRcKO mice displayed worse cardiac remodeling compared to control (GRf/f) mice, including a greater increase in heart weight to body weight ratio with a greater increase in cardiomyocytes size, a greater decline in left ventricular contractility, and higher reactivation of fetal genes. MRcKO mice showed a comparable degree of cardiac remodeling compared to control (MRf/f) mice. The worse cardiac remodeling in pressure overloaded GRcKO mice is not due to compensatory activation of cardiomyocyte MR, since pressure overloaded GRMRdcKO mice displayed cardiac remodeling to the same extent as GRcKO mice. Pressure overload suppressed GR-target gene expression in the heart. Although plasma corticosterone levels and subcellular localization of GR (nuclear/cytoplasmic GR) were not changed, a chromatin immunoprecipitation assay revealed that GR recruitment onto the promoter of GR-target genes was significantly suppressed in response to pressure overload. Rescue of the expression of GR-target genes to the same extent as sham-operated hearts attenuated adverse cardiac remodeling in pressure-overloaded hearts. Thus, GR works as a repressor of adverse cardiac remodeling in response to pressure overload, but GR-mediated transcription is suppressed under pressure overload. Therapies that maintain GR-mediated transcription in cardiomyocytes under pressure overload can be a promising therapeutic strategy for heart failure.