Novel Role for Pleckstrin Homology-Like Domain Family A, Member 3 in the Regulation of Pathological Cardiac Hypertrophy.

Content Provider	Europe PMC
Author	Liu, Jia Liu, Xiaoxiong Hui, Xuejun Cai, Lin Li, Xuebo Yang, Yang Shu, Shangzhi Wang, Fan Xia, Hao Li, Shuyan
Abstract	BackgroundPleckstrin 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 ResultsIn 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‐GSK3β‐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.ConclusionsCollectively, 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.
Page Count	17
Journal	Journal of the American Heart Association
Volume Number	8
PubMed Central reference number	PMC6759890
Issue Number	16
PubMed reference number	31426686
e-ISSN	20479980
DOI	10.1161/jaha.118.011830
Language	English
Publisher	John Wiley and Sons Inc.
Publisher Date	2019-08-20
Publisher Place	Hoboken
Access Restriction	Open
Rights License	This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. © 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
Subject Keyword	AKT cardiac hypertrophy heart failure pleckstrin homology‐like domain family A, member 3 pressure overload signal transduction Heart Failure Hypertrophy Remodeling
Content Type	Text
Resource Type	Article
Subject	Cardiology and Cardiovascular Medicine