Novel Role for Pleckstrin Homology-Like Domain Family A , Member 3 in the Regulation of Pathological Cardiac Hypertrophy
Novel Role for Pleckstrin Homology-Like Domain Family A , Member 3 in the Regulation of Pathological Cardiac Hypertrophy
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Pleckstrin 同源样结构域家族 A 成员 3 在调节病理性心脏肥大中的新作用
DOI：
10.1161/jaha.118.011830
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发表时间：
2019-08-20
影响因子：
5.4
通讯作者：
Li, Shuyan
中科院分区：
文献类型：
--
作者：
Liu, Jia;Liu, Xiaoxiong;Li, Shuyan
背景：pleckstrin同源结构域家族A， member 3 （PHLDA3）是PHLDA家族的重要成员，参与肿瘤抑制、肾损伤、肝损伤和葡萄糖代谢。然而，PHLDA3在病理性心脏肥厚和心力衰竭中的作用尚不清楚。方法与结果：在本研究中，PHLDA3在肥厚小鼠心脏和血管紧张素ii处理的心肌细胞中表达下调。接下来，一项体外研究表明，通过使用功能获得和功能丧失的方法，PHLDA3减轻了Ang II暴露诱导的心肌细胞肥大。与细胞表型一致，PHLDA3的破坏加重了压力过载引起的病理性心肌肥大、纤维化和功能障碍的影响。相反，PHLDA3过表达导致肥厚表型减弱。分子分析显示，PHLDA3抑制了肥大应激时AKT- mtor - gsk3 β - p70s6k信号的激活，阻断AKT激活可在体内和体外分别挽救AB和Ang II诱导的PHLDA3缺陷的这些不良病理效应。综上所述，我们的数据表明PHLDA3主要通过阻断AKT信号通路来改善压力超负荷引起的心脏重构，这表明PHLDA3可能是治疗病理性心脏肥厚和心力衰竭的治疗靶点。
Background-Pleckstrin homology-like domain family A, member 3 (PHLDA3), a crucial member of the PHLDA family, is involved in tumor suppression, kidney injury, liver injury, and glucose metabolism. However, the role of PHLDA3 in pathological cardiac hypertrophy and heart failure remains unclear.Methods and Results-In the present study, PHLDA3 expression was downregulated in hypertrophic murine hearts and angiotensin II-treated cardiomyocytes. Next, an in vitro study suggested, by using gain- and loss-of-function approaches, that PHLDA3 attenuates Ang II exposure-induced cardiomyocyte hypertrophy. Consistent with the cell phenotype, disruption of PHLDA3 aggravated the effects of pressure overload-induced pathological cardiac hypertrophy, fibrosis, and dysfunction. In contrast, PHLDA3 overexpression resulted in an attenuated hypertrophic phenotype. Molecular analysis revealed that PHLDA3 suppressed the activation of AKT-mTOR-GSK3 beta-P70S6K signaling in response to hypertrophic stress, and the blockage of AKT activation rescued these adverse pathological effects of PHLDA3 deficiency-induced by AB and Ang II, respectively, in vivo and in vitro.Conclusions-Collectively, our data indicated that PHLDA3 could ameliorate pressure overload-induced cardiac remodeling mainly by blocking the AKT signaling pathway, suggesting that PHLDA3 may represent a therapeutic target for the treatment of pathological cardiac hypertrophy and heart failure.