Novel Role for Pleckstrin Homology‐Like Domain Family A, Member 3 in the Regulation of Pathological Cardiac Hypertrophy
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. Meth...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-08-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.118.011830 |
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| author | Jia Liu Xiaoxiong Liu Xuejun Hui Lin Cai Xuebo Li Yang Yang Shangzhi Shu Fan Wang Hao Xia Shuyan Li |
| author_facet | Jia Liu Xiaoxiong Liu Xuejun Hui Lin Cai Xuebo Li Yang Yang Shangzhi Shu Fan Wang Hao Xia Shuyan Li |
| author_sort | Jia Liu |
| collection | DOAJ |
| description | 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‐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. 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. |
| first_indexed | 2024-04-13T16:39:44Z |
| format | Article |
| id | doaj.art-20de3e843e31408db25b02565850b9d3 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-13T16:39:44Z |
| publishDate | 2019-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-20de3e843e31408db25b02565850b9d32022-12-22T02:39:17ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802019-08-0181610.1161/JAHA.118.011830Novel Role for Pleckstrin Homology‐Like Domain Family A, Member 3 in the Regulation of Pathological Cardiac HypertrophyJia Liu0Xiaoxiong Liu1Xuejun Hui2Lin Cai3Xuebo Li4Yang Yang5Shangzhi Shu6Fan Wang7Hao Xia8Shuyan Li9Department of Cardiology First Hospital of Jilin University Changchun Jilin ChinaDepartment of Cardiology Renmin Hospital of Wuhan University Wuhan ChinaDepartment of Cardiology Second Hospital of Jilin University Changchun Jilin ChinaZhongnan Hospital of Wuhan University Wuhan ChinaDepartment of Cardiology First Hospital of Jilin University Changchun Jilin ChinaDepartment of Cardiology First Hospital of Jilin University Changchun Jilin ChinaDepartment of Cardiology First Hospital of Jilin University Changchun Jilin ChinaDepartment of Cardiology First Hospital of Jilin University Changchun Jilin ChinaDepartment of Cardiology Renmin Hospital of Wuhan University Wuhan ChinaDepartment of Cardiology First Hospital of Jilin University Changchun Jilin ChinaBackground 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‐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. 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.https://www.ahajournals.org/doi/10.1161/JAHA.118.011830AKTcardiac hypertrophyheart failurepleckstrin homology‐like domain family A, member 3pressure overloadsignal transduction |
| spellingShingle | Jia Liu Xiaoxiong Liu Xuejun Hui Lin Cai Xuebo Li Yang Yang Shangzhi Shu Fan Wang Hao Xia Shuyan Li Novel Role for Pleckstrin Homology‐Like Domain Family A, Member 3 in the Regulation of Pathological Cardiac Hypertrophy Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease AKT cardiac hypertrophy heart failure pleckstrin homology‐like domain family A, member 3 pressure overload signal transduction |
| title | Novel Role for Pleckstrin Homology‐Like Domain Family A, Member 3 in the Regulation of Pathological Cardiac Hypertrophy |
| title_full | Novel Role for Pleckstrin Homology‐Like Domain Family A, Member 3 in the Regulation of Pathological Cardiac Hypertrophy |
| title_fullStr | Novel Role for Pleckstrin Homology‐Like Domain Family A, Member 3 in the Regulation of Pathological Cardiac Hypertrophy |
| title_full_unstemmed | Novel Role for Pleckstrin Homology‐Like Domain Family A, Member 3 in the Regulation of Pathological Cardiac Hypertrophy |
| title_short | Novel Role for Pleckstrin Homology‐Like Domain Family A, Member 3 in the Regulation of Pathological Cardiac Hypertrophy |
| title_sort | novel role for pleckstrin homology like domain family a member 3 in the regulation of pathological cardiac hypertrophy |
| topic | AKT cardiac hypertrophy heart failure pleckstrin homology‐like domain family A, member 3 pressure overload signal transduction |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.118.011830 |
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