Yan Wen, Dong Zhi-Chao, Wang Jing-Jing, Zhang Yun-Long, Wang Hong-Xia, Zhang Bo, Li Hui-Hua
Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Front Physiol. 2020 Jun 9;11:625. doi: 10.3389/fphys.2020.00625. eCollection 2020.
BACKGROUND/AIM: Hypertensive cardiac hypertrophy is the leading cause of cardiac remodeling and heart failure. We recently demonstrated that the immunoproteasome, an inducible form of the constitutive proteasome, plays a critical role in regulating cardiovascular diseases. However, the role of the immunoproteasome LMP10 (β2i) catalytic subunit in the regulation of angiotensin II (Ang II)-induced cardiac hypertrophic remodeling remains unclear.
Wild-type (WT) and LMP10 knockout (KO) mice were infused with Ang II 1,000 ng/kg/min for 2 weeks. Blood pressure was measured using a tail-cuff system. Cardiac function and hypertrophic remodeling were examined by echocardiography and histological staining. The expression levels of genes and proteins were examined with quantitative real-time PCR and immunoblotting analysis, respectively.
LMP10 mRNA and protein expression was significantly increased in Ang II-stimulated hearts and primary cardiomyocytes. Moreover, Ang II infusion for 2 weeks increased systolic blood pressure, abnormal cardiac function, hypertrophy, fibrosis, and inflammation in WT mice, which were significantly reversed in KO mice. Moreover, a marked reduction in the protein levels of insulin growth factor-1 receptor (IGF1R), glycoprotein 130 (gp130), and phosphorylated AKT, mTOR, STAT3, and ERK1/2 and an increase in the LC3II/I ratio were also observed in LMP10 KO mice compared with WT mice after Ang II infusion. culture experiments confirmed that LMP10 knockdown activated autophagy and increased IGF1R and gp130 degradation, leading to the inhibition of cardiomyocyte hypertrophy. However, inhibiting autophagy with chloroquine reversed this effect.
The results of this study indicate that LMP10 KO attenuates Ang II-induced cardiac hypertrophic remodeling via the autophagy-dependent degradation of IGF1R and gp130, and suggests that LMP10 may be a novel therapeutic target for hypertrophic heart diseases.
背景/目的：高血压性心肌肥厚是心脏重塑和心力衰竭的主要原因。我们最近证明，免疫蛋白酶体是组成型蛋白酶体的一种可诱导形式，在调节心血管疾病中起关键作用。然而，免疫蛋白酶体LMP10（β2i）催化亚基在调节血管紧张素II（Ang II）诱导的心脏肥厚性重塑中的作用仍不清楚。
野生型（WT）和LMP10基因敲除（KO）小鼠以1000 ng/kg/min的剂量输注Ang II，持续2周。使用尾袖带系统测量血压。通过超声心动图和组织学染色检查心脏功能和肥厚性重塑。分别用定量实时PCR和免疫印迹分析检测基因和蛋白质的表达水平。
在Ang II刺激的心脏和原代心肌细胞中，LMP10 mRNA和蛋白质表达显著增加。此外，WT小鼠输注Ang II 2周会导致收缩压升高、心脏功能异常、肥厚、纤维化和炎症，而这些在KO小鼠中得到显著逆转。此外，与输注Ang II后的WT小鼠相比，LMP10 KO小鼠中胰岛素生长因子-1受体（IGF1R）、糖蛋白130（gp130）以及磷酸化的AKT、mTOR、STAT3和ERK1/2的蛋白水平显著降低，且LC3II/I比值升高。培养实验证实，LMP10基因敲低激活了自噬并增加了IGF1R和gp130的降解，从而抑制了心肌细胞肥大。然而，用氯喹抑制自噬可逆转这种作用。
本研究结果表明，LMP10基因敲除通过自噬依赖性降解IGF1R和gp130减轻了Ang II诱导的心脏肥厚性重塑，并提示LMP10可能是肥厚性心脏病的一个新的治疗靶点。
