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.
Highlights
Research has demonstrated that hypoxic preconditioning (HP) can enhance the survival and proliferation of cardiac progenitor cells (CPCs); the underlying mechanisms are not fully understood
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
The present study reports that HP of CPCs represses p53 by activating the PI3k/Akt pathway and up-regulating DNMT1 and DNMT3β
Summary
Research has demonstrated that hypoxic preconditioning (HP) can enhance the survival and proliferation of cardiac progenitor cells (CPCs); the underlying mechanisms are not fully understood. Cardiac progenitor cell (CPC) transplantation, maybe a promising novel approach for treating patients with advanced heart failure caused by AMI. Among these CPCs, c-kit-positive CPCs exhibit enhanced proliferation and differentiation abilities to repair injured myocardium and are the most promising candidates for cell therapy for CHF3,4. Many reports have demonstrated that the pro-survival function of Akt is activated as a mediator of the preconditioning signal by hypoxia in various cell types[10,11]. Many studies in recent years have indicated that p53 activation plays a critical role in damaged www.nature.com/scientificreports/
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