Open AccessNovel Role for Pleckstrin Homology‐Like Domain Family A, Member 3 in the Regulation of Pathological Cardiac Hypertrophy
Author(s) -
Liu Jia,
Liu Xiaoxiong,
Hui Xuejun,
Cai Lin,
Li Xuebo,
Yang Yang,
Shu Shangzhi,
Wang Fan,
Xia Hao,
Li Shuyan
Publication year - 2019
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.118.011830
Subject(s) - pleckstrin homology domain , medicine , muscle hypertrophy , protein kinase b , pressure overload , heart failure , angiotensin ii , fibrosis , endocrinology , pi3k/akt/mtor pathway , pathological , signal transduction , microbiology and biotechnology , biology , receptor , cardiac hypertrophy
Background Pleckstrin homology‐like domain family A, member 3 ( PHLDA 3), a crucial member of the PHLDA family, is involved in tumor suppression, kidney injury, liver injury, and glucose metabolism. However, the role of PHLDA 3 in pathological cardiac hypertrophy and heart failure remains unclear. Methods and Results In the present study, PHLDA 3 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 PHLDA 3 attenuates Ang II exposure‐induced cardiomyocyte hypertrophy. Consistent with the cell phenotype, disruption of PHLDA 3 aggravated the effects of pressure overload‐induced pathological cardiac hypertrophy, fibrosis, and dysfunction. In contrast, PHLDA 3 overexpression resulted in an attenuated hypertrophic phenotype. Molecular analysis revealed that PHLDA 3 suppressed the activation of AKT ‐ mTOR ‐ GSK 3β‐P70S6K signaling in response to hypertrophic stress, and the blockage of AKT activation rescued these adverse pathological effects of PHLDA 3 deficiency‐induced by AB and Ang II , respectively, in vivo and in vitro. Conclusions Collectively, our data indicated that PHLDA 3 could ameliorate pressure overload‐induced cardiac remodeling mainly by blocking the AKT signaling pathway, suggesting that PHLDA 3 may represent a therapeutic target for the treatment of pathological cardiac hypertrophy and heart failure.