Inhibition of PHLPP1 ameliorates cardiac dysfunction via activation of the PI3K/Akt/mTOR signalling pathway in diabetic cardiomyopathy
Inhibition of PHLPP1 ameliorates cardiac dysfunction via activation of the PI3K/Akt/mTOR signalling pathway in diabetic cardiomyopathy
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糖尿病心肌病中 PHLPP1 的抑制通过激活 PI3K/Akt/mTOR 信号通路改善心功能障碍
DOI：
10.1111/jcmm.15123
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发表时间：
2020-03-09
影响因子：
5.3
通讯作者：
An, Fengshuang
中科院分区：
文献类型：
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作者：
Zhang, Mingjun;Wang, Xuyang;An, Fengshuang
背景 Pleckstrin 同源 (PH) 结构域富含亮氨酸重复蛋白磷酸酶 1 (PHLPP1) 是一种丝氨酸/苏氨酸磷酸酶，其失调与多种人类疾病相伴。然而，其在糖尿病心肌病中的作用仍不清楚。我们探讨了PHLPP1在糖尿病心肌病(DCM)中的潜在功能和机制。方法通过腹腔注射60 mg/kg链脲佐菌素(STZ)体内诱导1型糖尿病大鼠。慢病毒介导的短发夹 RNA (shRNA) 用于敲低 PHLPP1 的表达。在体外，原代新生大鼠心肌细胞和H9C2细胞在5.5 mmol/L葡萄糖（正常葡萄糖，NG）或33.3 mmol/L葡萄糖（高葡萄糖，HG）中孵育。通过PHLPP1-siRNA抑制PHLPP1表达，探讨PHLPP1在高糖诱导H9c2细胞凋亡中的功能。结果糖尿病大鼠PHLPP1表达上调，左心功能不全，心肌细胞凋亡和纤维化增加。 PHLPP1 抑制可减轻心脏功能障碍。此外，PHLPP1 抑制显着减少了 HG 诱导的细胞凋亡，并恢复了 H9c2 细胞中 PI3K/AKT/mTOR 通路的活性。此外，用PI3K/Akt/mTOR通路抑制剂LY294002进行预处理，消除了PHLPP1抑制的抗细胞凋亡作用。结论我们的研究表明，PHLPP1抑制通过激活PI3K/Akt/mTOR信号通路减轻了DCM中的心功能障碍。因此，PHLPP1可能成为人类DCM的新治疗靶点。
Background Pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase 1 (PHLPP1) is a kind of serine/threonine phosphatase, whose dysregulation is accompanied with numerous human diseases. However, its role in diabetic cardiomyopathy remains unclear. We explored the underlying function and mechanism of PHLPP1 in diabetic cardiomyopathy (DCM).Method In vivo, Type 1 diabetic rats were induced by intraperitoneal injection of 60 mg/kg streptozotocin (STZ). Lentivirus-mediated short hairpin RNA (shRNA) was used to knock down the expression of PHLPP1. In vitro, primary neonatal rat cardiomyocytes and H9C2 cells were incubated in 5.5 mmol/L glucose (normal glucose, NG) or 33.3 mmol/L glucose (high glucose, HG). PHLPP1 expression was inhibited by PHLPP1-siRNA to probe into the function of PHLPP1 in high glucose-induced apoptosis in H9c2 cells.Results Diabetic rats showed up-regulated PHLPP1 expression, left ventricular dysfunction, increased myocardial apoptosis and fibrosis. PHLPP1 inhibition alleviated cardiac dysfunction. Additionally, PHLPP1 inhibition significantly reduced HG-induced apoptosis and restored PI3K/AKT/mTOR pathway activity in H9c2 cells. Furthermore, pretreatment with LY294002, an inhibitor of PI3K/Akt/mTOR pathway, abolished the anti-apoptotic effect of PHLPP1 inhibition.Conclusion Our study indicated that PHLPP1 inhibition alleviated cardiac dysfunction via activating the PI3K/Akt/mTOR signalling pathway in DCM. Therefore, PHLPP1 may be a novel therapeutic target for human DCM.