PHLPP1 deficiency ameliorates cardiomyocyte death and cardiac dysfunction through inhibiting Mcl-1 degradation.

Yong Tan, Tong Li, Meiling Hu, Bo Wang, Qingqing Zhou, Yuyu Jiang, Sheng Zhang, Xuewen Duan, Junqi Yang, Xingguang Liu, Zhenzhen Zhan

Cellular signalling 2022 Apr

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Myocardial infarction (MI), ischemia-reperfusion injury or chemotherapy can trigger excessive loss of terminally differentiated cardiomyocytes, leading to the development of heart failure. Whereas apoptosis has been considered to be the major form of cell death in various myocardial damage, the means by which to reduce cardiomyocyte loss are limited, and the mechanism that underlies cardiomyocyte apoptosis need to be further investigated. PH domain leucine-rich repeat protein phosphatase1 (PHLPP1) belongs to a novel family of Ser/Thr protein phosphatases that functions as a tumor suppressor. Here, we identified PHLPP1 as an important pro-apoptosis factor of cardiomyocytes in response to pathogenic stresses. The conditional PHLPP1 deficiency in cardiomyocytes alleviated myocardial ischemic injury, improved cardiac function and inhibited myocardial fibrosis, in turn preventing adverse cardiac remodeling and heart failure after MI. The conditional PHLPP1 deficiency in cardiomyocytes also attenuated doxorubicin (Dox)-induced myocardial injury, suppressed the inflammation and fibrosis in cardiac tissues, and protected from cardiac dysfunction. Mechanically, PHLPP1 bound the anti-apoptosis protein myeloid cell leukemia sequence 1 (Mcl-1) in cardiomyocytes. Thr163 phosphorylation of Mcl-1 was reported to slow Mcl-1 protein turnover. We further found that PHLPP1 deficiency enhanced Thr163 phosphorylation of Mcl-1, inhibited Mcl-1 degradation and maintained Mcl-1 protein expression level in myocardium and cardiomyocytes upon MI or Dox treatment. PHLPP1 could directly dephosphorylate Thr163 of Mcl-1. Thus, PHLPP1 promotes cardiomyocyte death and cardiac dysfunction through binding and enhancing Mcl-1 degradation under ischemic or toxic injury conditions, which sheds new light on the development of potential therapies to control cardiomyocyte loss. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Yong Tan, Tong Li, Meiling Hu, Bo Wang, Qingqing Zhou, Yuyu Jiang, Sheng Zhang, Xuewen Duan, Junqi Yang, Xingguang Liu, Zhenzhen Zhan. PHLPP1 deficiency ameliorates cardiomyocyte death and cardiac dysfunction through inhibiting Mcl-1 degradation. Cellular signalling. 2022 Apr;92:110281