Nuclear Tkt promotes ischemic heart failure via the cleaved Parp1/Aif axis.

Abstract

Transketolase (Tkt), an enzyme in pentose phosphate pathway, has been reported to regulate genome instability and cell survival in cancers. Yet, the role of Tkt after myocardial ischemic injury remains to be elucidated. Label-free proteomics revealed dramatic elevation of Tkt in murine hearts after myocardial infarction (MI). Lentivirus-mediated Tkt knockdown ameliorated cardiomyocyte apoptosis and preserved the systolic function after myocardial ischemic injury. In contrast, Tkt overexpression led to the opposite effects. Inducible conditional cardiomyocyte Tkt-knockout mice were generated, and cardiomyocyte-expressed Tkt was found to play an intrinsic role in the ischemic heart failure of these model mice. Furthermore, through luciferase assay and chromatin immunoprecipitation, Tkt was shown to be a direct target of transcription factor Krüppel-like factor 5 (Klf5). In cardiomyocytes under ischemic stress, Tkt redistributed into the nucleus. By binding with the full-length poly(ADP-ribose) polymerase 1 (Parp1), facilitating its cleavage, and activating apoptosis inducible factor (Aif) subsequently, nuclear Tkt demonstrated its non-metabolic functions. Overall, our study confirmed that elevated nuclear Tkt plays a noncanonical role in promoting cardiomyocyte apoptosis via the cleaved Parp1/Aif pathway, leading to the deterioration of cardiac dysfunction.

• Authors: Zhiyan Wang, Zeping Qiu, Sha Hua, Wenbo Yang, Yanjia Chen, Fanyi Huang, Yingze Fan, Lingfeng Tong, Tianle Xu, Xuemei Tong, Ke Yang, Wei Jin
• Journal: Basic research in cardiology (Basic Res Cardiol) Vol. 117 Issue 1 Pg. 18 (04 05 2022) ISSN: 1435-1803 [Electronic] Germany
• PMID: 35380314 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.

Chemical References

• Apoptosis Inducing Factor
• AIFM1 protein, mouse
• Transketolase
• Parp1 protein, mouse
• Poly (ADP-Ribose) Polymerase-1

Topics

• Animals
• Apoptosis
• Apoptosis Inducing Factor
• Heart Failure (genetics, metabolism)
• Mice
• Myocardial Infarction (metabolism)
• Myocytes, Cardiac (metabolism)
• Poly (ADP-Ribose) Polymerase-1
• Transketolase (metabolism)