Liu Shuang, Liu Li-Xin, Zhang Yun-Long, Lai Song, Xie Yun-Peng, Li Nan-Nan, Wang Hong-Xia, Xia Yun-Long, Liu Ying, Li Hui-Hua
Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, Dalian, China.
Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Cell Physiol Biochem. 2018;47(1):140-150. doi: 10.1159/000489757. Epub 2018 May 10.
BACKGROUND/AIMS: Cardiac remodeling is a critical pathogenetic process leading to heart failure. Suppressor of cytokine signaling-3 (SOCS3) is demonstrated as a key negative regulator of the gp130 receptor to inhibit cardiac hypertrophy. However, the role of SOCS3 in deoxycorticosterone-acetate (DOCA)-salt-induced cardiac remodeling remains unclear.
Cardiac-specific SOCS3 knockout (SOCS3cKO) and wild-type (WT) C57BL/6J mice were subjected to uninephrectomy and DOCA-salt for 3 weeks. The effect of SOCS3 on cardiac remodeling and inflammation was evaluated by histological analysis. Gene and protein levels were measured by real-time PCR and immunoblotting analysis.
After DOCA-salt treatment, the expression of SOCS3, activation of gp130/JAK/STAT3, cardiac dysfunction and fibrosis in DOCA-salt mice were significantly elevated, which were markedly attenuated by eplerenone, a specific mineralocorticoid receptor (MR) blocker. Moreover, DOCA-salt-induced cardiac dysfunction, hypertrophy, fibrosis and inflammation were aggravated in SOCS3cKO mice, but were significantly reduced in AAV9-SOCS3-injected mice. These effects were mostly associated with activation of gp130/STAT3/AKT/ERK1/2, TGF-β/Smad2/3 and NF-κB signaling pathways.
Our data demonstrate that loss of SOCS3 in cardiomyocytes promotes DOCA-salt-induced cardiac remodeling and inflammation, and it may be a novel potential therapeutic target for hypertensive heart disease.
背景/目的：心脏重塑是导致心力衰竭的关键发病机制过程。细胞因子信号转导抑制因子3（SOCS3）被证明是gp130受体的关键负调节因子，可抑制心脏肥大。然而，SOCS3在脱氧皮质酮醋酸盐（DOCA）-盐诱导的心脏重塑中的作用仍不清楚。
将心脏特异性SOCS3基因敲除（SOCS3cKO）和野生型（WT）C57BL/6J小鼠进行单侧肾切除并给予DOCA-盐处理3周。通过组织学分析评估SOCS3对心脏重塑和炎症的影响。通过实时PCR和免疫印迹分析测量基因和蛋白质水平。
DOCA-盐处理后，DOCA-盐小鼠中SOCS3的表达、gp130/JAK/STAT3的激活、心脏功能障碍和纤维化显著升高，而特异性盐皮质激素受体（MR）阻滞剂依普利酮可明显减轻这些变化。此外，DOCA-盐诱导的心脏功能障碍、肥大、纤维化和炎症在SOCS3cKO小鼠中加重，但在注射AAV9-SOCS3的小鼠中显著减轻。这些作用大多与gp130/STAT3/AKT/ERK1/2、TGF-β/Smad2/3和NF-κB信号通路的激活有关。
我们的数据表明，心肌细胞中SOCS3的缺失促进了DOCA-盐诱导的心脏重塑和炎症，它可能是高血压性心脏病的一个新的潜在治疗靶点。
