Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation.

Abstract

Serine/threonine kinases (STK3) is a core component of the Hippo pathway and modulates oxidative stress and inflammatory responses in cardiovascular diseases. However, its potential role in septic cardiomyopathy remains undefined. STK3-mediated phosphorylation of Kelch-like ECH-associated protein 1 (KEAP1) was shown to suppress antioxidant gene transcription controlled by nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages. To explore whether STK3 induces KEAP1-mediated suppression of Nrf2 in septic cardiomyopathy, wild-type and global STK3 knockout (STK3 -/- ) mice were treated with LPS. LPS treatment upregulated cardiac STK3 expression. STK3 deletion attenuated myocardial inflammation and cardiomyocyte death, and improved myocardial structure and function. In LPS-challenged HL-1 cardiomyocytes, shRNA-mediated STK3 knockdown normalized mitochondrial membrane potential and ATP production, attenuated apoptosis, and rescued antioxidant gene expression by preventing Nrf2 downregulation. Co-IP, docking analysis, western blotting, and immunofluorescence assays further showed that STK3 binds and phosphorylates KEAP1, promoting Nrf2 downregulation. Accordingly, transfection of phosphodefective KEAP1 mutant protein in cardiomyocyte restored Nrf2 expression and mitochondrial performance upon LPS, while expression of a phosphomimetic KEAP1 mutant abolished the mitochondria-protective and pro-survival effects of STK3 deletion. These findings suggest that STK3 upregulation contributes to septic cardiomyopathy by phosphorylating KEAP1 to promote Nrf2 degradation and suppression of the antioxidant response.

• Authors: Hang Zhu, Zhe Dai, Xiaoman Liu, Hao Zhou, Yijin Wang
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 19 Issue 5 Pg. 1369-1381 ( 2023) ISSN: 1449-2288 [Electronic] Australia
• PMID: 37056939 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Antioxidants
• Kelch-Like ECH-Associated Protein 1
• Lipopolysaccharides
• NF-E2-Related Factor 2
• Protein Serine-Threonine Kinases
• Serine
• Serine-Threonine Kinase 3
• Stk3 protein, mouse

Topics

• Animals
• Mice
• Antioxidants (metabolism)
• Cardiomyopathies (genetics)
• Kelch-Like ECH-Associated Protein 1 (genetics, metabolism)
• Lipopolysaccharides (toxicity)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Oxidative Stress
• Phosphorylation
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Serine
• Serine-Threonine Kinase 3