Hypoxia induces hypomethylation of the HMGB1 promoter via the MAPK/DNMT1/HMGB1 pathway in cardiac progenitor cells.

Abstract

Apoptosis is involved in the death of cardiac progenitor cells (CPCs) after myocardial infarction (MI) in the heart. The loss of CPCs results in infarct scar and further deterioration of the heart function. Though stem cell-based therapy provides an effective approach for heart function recovery after MI, the retention of CPCs in the infarcted area of the heart is the main barrier that limits its promising therapy. Therefore, the underlying mechanisms of CPC apoptosis in hypoxia are important for the development of new therapeutic targets for MI patients. In this work, we found that the expression of high-mobility group box 1(HMGB1) was upregulated in CPCs under hypoxia conditions. Further study demonstrated that HMGB1 was regulated by DNA methyltransferases 1 (DNMT1) via changing the methylation state of CpGs in the promoter of HMGB1 in CPCs during hypoxia process. Additionally, mitogen-activated protein kinase (MAPK) signaling pathway was found to be involved in regulating DNMT1/HMGB1-mediated CPC apoptosis in hypoxia process. In conclusion, our findings demonstrate a novel regulatory mechanism for CPC apoptosis and proliferation under hypoxia conditions, which may provide a new therapeutic approach for MI patients.

• Authors: Jinwen Su, Ming Fang, Bei Tian, Jun Luo, Can Jin, Xuejun Wang, Zhongping Ning, Xinming Li
• Journal: Acta biochimica et biophysica Sinica (Acta Biochim Biophys Sin (Shanghai)) Vol. 50 Issue 11 Pg. 1121-1130 (Nov 01 2018) ISSN: 1745-7270 [Electronic] China
• PMID: 30307477 (Publication Type: Journal Article)

Chemical References

• HMGB1 Protein
• DNA (Cytosine-5-)-Methyltransferase 1
• Dnmt1 protein, mouse
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Apoptosis (genetics)
• Cell Hypoxia
• Cell Survival (genetics)
• Cells, Cultured
• DNA (Cytosine-5-)-Methyltransferase 1 (genetics, metabolism)
• DNA Methylation
• HMGB1 Protein (genetics, metabolism)
• Humans
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Myocytes, Cardiac (cytology, metabolism)
• Promoter Regions, Genetic (genetics)
• RNA Interference
• Signal Transduction (genetics)
• Stem Cells (cytology, metabolism)