Hypoxic Preconditioning Inhibits Hypoxia-induced Apoptosis of Cardiac Progenitor Cells via the PI3K/Akt-DNMT1-p53 Pathway

Citations Over TimeTop 13% of 2016 papers

Abstract

Research has demonstrated that hypoxic preconditioning (HP) can enhance the survival and proliferation of cardiac progenitor cells (CPCs); however, the underlying mechanisms are not fully understood. Here, we report that HP of c-kit (+) CPCs inhibits p53 via the PI3K/Akt-DNMT1 pathway. First, CPCs were isolated from the hearts of C57BL/6 mice and further purified by magnetic-activated cell sorting. Next, these cells were cultured under either normoxia (H0) or HP for 6 hours (H6) followed by oxygen-serum deprivation for 24 hours (24h). Flow cytometric analysis and MTT assays revealed that hypoxia-preconditioned CPCs exhibited an increased survival rate. Western blot and quantitative real-time PCR assays showed that p53 was obviously inhibited, while DNMT1 and DNMT3β were both significantly up-regulated by HP. Bisulphite sequencing analysis indicated that DNMT1 and DNMT3β did not cause p53 promoter hypermethylation. A reporter gene assay and chromatin immunoprecipitation analysis further demonstrated that DNMT1 bound to the promoter locus of p53 in hypoxia-preconditioned CPCs. Together, these observations suggest that HP of CPCs could lead to p53 inhibition by up-regulating DNMT1 and DNMT3β, which does not result in p53 promoter hypermethylation, and that DNMT1 might directly repress p53, at least in part, by binding to the p53 promoter locus.

Related Papers

• → FoxO Transcription Factors Promote AKT Ser473 Phosphorylation and Renal Tumor Growth in Response to Pharmacologic Inhibition of the PI3K–AKT Pathway(2014)162 cited
• → Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects(2013)21 cited
• → Virtual Docking Screening and QSAR Studies to Explore PI3K and mTOR Inhibitors Acting on AKT in Cancers(2020)1 cited
• → Solanine Interferes with AKT/p-AKT and PI3K/p-PI3K Pathway to Inhibit HIF and Destroy Cell Energy Metabolism(2021)1 cited
• → Solanine Interferes With AKT/p-AKT and PI3K/ p-PI3K to Inhibit HIF and Destroy Cell Energy Metabolism(2021)