Abstract
Circulating endothelial progenitor cells (EPCs) have multiple protective effects that facilitate repair of damage to tissues and organs. However, while various stressors are known to impair EPC function, the mechanisms of oxidative stress-induced EPC senescence remains unknown. We demonstrated that B2 receptor (B2R) expression on circulating CD34(+) cells was significantly reduced in patients with diabetes mellitus (DM) as compared to healthy controls. Furthermore, CD34(+) cell B2R expression in patients with DM was inversely correlated with plasma myeloperoxidase concentrations. Bradykinin (BK) treatment decreased human EPC (hEPC) senescence and intracellular oxygen radical production, resulting in reduced retinoblastoma 1 (RB) RNA expression in H2O2-induced senescent hEPCs and a reversal of the B2R downregulation that is normally observed in senescent cells. Furthermore, BK treatment of H2O2-exposed cells leads to elevated phosphorylation of RB, AKT, and cyclin D1 compared with H2O2-treatment alone. Antagonists of B2R, PI3K, and EGFR signaling pathways and B2R siRNA blocked BK protective effects. In summary, this study demonstrates that BK significantly inhibits oxidative stress-induced hEPC senescence though B2R-mediated activation of PI3K and EGFR signaling pathways.
Highlights
Endothelial progenitor cells (EPCs) are adult stem cells that exist within the vascular circulation and have numerous protective effects due to their ability to differentiate into endothelial cells, repair vascular intima injury, and promote angiogenesis post myocardial infarction [1]
Double staining for fluorescein isothiocyanate (FITC)-lectin and acLDL-Dil showed that human EPCs were able to uptake acLDL-Dil, which binds to an endothelial cellspecific lectin
Immunofluorescence showed that these human EPC (hEPC) expressed CD34, kinase domain receptor (KDR), and CD105, but not CD45. hEPCs were immunopositive for CD34, KDR, CD105, and B2 receptor (B2R), but not CD45 by flow cytometry (Figure 2)
Summary
Endothelial progenitor cells (EPCs) are adult stem cells that exist within the vascular circulation and have numerous protective effects due to their ability to differentiate into endothelial cells, repair vascular intima injury, and promote angiogenesis post myocardial infarction [1]. Stress-induced premature (SIP) senescence of EPCs caused by oxidative stress related to coronary artery disease and diabetes can impair their function, leading to harmful outcomes. Research has shown that decreases in the quantity and quality of EPCs can lead to enhanced progression of diabetes [2]. Numerous studies on the mechanisms of cellular senescence utilizing tumor cells and immortalized cell lines have revealed that retinoblastoma 1 (RB) plays a key role in cell senescence by suppressing the expression of genes involved in DNA replication [3]. While oxidative stress can induce cell senescence via the RB signaling pathway, the mechanism of EPC senescence induced by oxidative stress remains unknown [4, 5]
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