SDF-1alpha/CXCR4 decreases endothelial progenitor cells apoptosis under serum deprivation by PI3K/Akt/eNOS pathway
Hao Zheng1, Tao Dai, Binquan Zhou
1Department of Cardiology, Biomedical Research (Therapy) Center, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, Zhejiang Province, China.
Abstract:
Recent studies have demonstrated that stromal cell-derived factor-1alpha (SDF-1alpha)/CXCR4 interaction regulates multiple cell signal pathways and a variety of cellular functions such as cell migration, proliferation, survival and angiogenesis. In present study, we aimed to determine the effect of SDF-1alpha on endothelial progenitor cells (EPCs) apoptosis induced by serum deprivation and the implication of phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) signaling in this effect. EPCs were isolated and characterized. SDF-1alpha decreased EPCs apoptosis induced by serum deprivation in a dose-dependent manner and the inhibitory effect was CXCR4 dependent as confirmed by the total abolishment by AMD3100, a CXCR4-specific peptide antagonist. SDF-1alpha treatment also significant decreased caspase-3 expression and activity. The inhibitory effect of SDF-1alpha on EPCs apoptosis was nearly completely abolished by PI3K inhibitors (either Wortmannin or LY294002) and partially abolished by NOS inhibitor, N(G)-nitro-arginine methyl ester, whereas inhibitors of MAPKs had no significant effect on this inhibitory effect. The treatment of EPCs with SDF-1alpha resulted in time-dependent Akt, eNOS, extracellular-regulated kinase (ERK1/2), p38 MAPK and c-Jun N-terminal kinase (JNK) phosphorylations. These findings suggest that PI3K/Akt/eNOS activation, but not MAPKs activation, is required for the inhibitory effect of SDF-1alpha on EPCs apoptosis.
Insights
Stromal cell-derived factor-1alpha (SDF-1alpha) inhibits apoptosis in endothelial progenitor cells (EPCs) via CXCR4 signaling. The PI3K/Akt/eNOS pathway, not MAPKs, mediates this protective effect.
Area of Science:
- Cell Biology
- Molecular Biology
- Cardiovascular Research
Background:
- Stromal cell-derived factor-1alpha (SDF-1alpha) and its receptor CXCR4 are crucial regulators of cellular functions, including migration, proliferation, survival, and angiogenesis.
- Endothelial progenitor cells (EPCs) play a vital role in vascular repair and neovascularization.
Purpose of the Study:
- To investigate the effect of SDF-1alpha on serum deprivation-induced apoptosis in EPCs.
- To elucidate the involvement of phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) signaling pathways in this process.
Main Methods:
- EPCs were isolated and characterized.
- Cells were treated with varying concentrations of SDF-1alpha and specific pathway inhibitors (AMD3100, Wortmannin, LY294002, N(G)-nitro-arginine methyl ester, MAPK inhibitors).
- Apoptosis, caspase-3 activity, and protein phosphorylation (Akt, eNOS, ERK1/2, p38 MAPK, JNK) were assessed.
Main Results:
- SDF-1alpha dose-dependently reduced serum deprivation-induced EPC apoptosis, an effect blocked by the CXCR4 antagonist AMD3100.
- SDF-1alpha significantly decreased caspase-3 expression and activity.
- The anti-apoptotic effect was abolished by PI3K inhibitors and partially by an NOS inhibitor, but not by MAPK inhibitors.
- SDF-1alpha induced time-dependent phosphorylation of Akt, eNOS, ERK1/2, p38 MAPK, and JNK.
Conclusions:
- SDF-1alpha protects EPCs from serum deprivation-induced apoptosis through a CXCR4-dependent mechanism.
- The PI3K/Akt/eNOS signaling pathway is essential for mediating the anti-apoptotic effects of SDF-1alpha on EPCs.
- MAPK signaling pathways are not critically involved in SDF-1alpha's protective role against EPC apoptosis in this context.
