Reverse-D-4F Increases the Number of Endothelial Progenitor Cells and Improves Endothelial Progenitor Cell Dysfunctions in High Fat Diet Mice

Abstract

Although high density lipoprotein (HDL) improves the functions of endothelial progenitor cells (EPCs), the effect of HDL ApoAI mimetic peptide reverse-D-4F (Rev-D4F) on EPC mobilization and repair of EPC dysfunctions remains to be studied. In this study, we investigated the effects of Rev-D4F on peripheral blood cell subpopulations in C57 mice treated with a high fat diet and the mechanism of Rev-D4F in improving the function of EPCs impaired by tumor necrosis factor-α (TNF-α). The high fat diet significantly decreased the number of EPCs, EPC migratory functions, and the percentage of lymphocytes in the white blood cells. However, it significantly increased the number of white blood cells, the percentage of monocytes in the white blood cells, and the level of vascular endothelial growth factor (VEGF) and TNF-α in the plasma. Rev-D4F clearly inhibited the effect of the high fat diet on the quantification of peripheral blood cell subpopulations and cytokine levels, and increased stromal cell derived factor 1α (SDF-1α) in the plasma. We provided in vitro evidence that TNF-α impaired EPC proliferation, migration, and tube formation through inactive AKT and eNOS, which was restored by Rev-D4F treatment. In contrast, both the PI3-kinase (PI3K) inhibitor (LY294002) and AKT inhibitor (perifosine) obviously inhibited the restoration of Rev-4F on EPCs impaired by TNF-α. Our results suggested that Rev-D4F increases the quantity of endothelial progenitor cells through increasing the SDF-1α levels and decreasing the TNF-α level of peripheral blood in high fat diet-induced C57BL/6J mice, and restores TNF-α induced dysfunctions of EPCs partly through stimulating the PI3K/AKT signal pathway.

Role of PI3K in the Progression and Regression of Atherosclerosis

“…Increasing the number, regeneration and function of EPCs could promote the repair of damaged endothelial cell monolayers and inhibit mesangial SMC activity and neointima formation, thereby inhibiting atherosclerosis; statins and olmesartan mobilized EPCs in the bone marrow and inhibited endothelial progenitor cell apoptosis through the PI3K/Akt pathways, increasing the number of EPCs in the blood circulation and repairing damaged endothelial cells ( Dimmeler et al, 2001 ; Gong et al, 2015 ). Reverse-D-4F improved high-fat diet-induced bone marrow-derived EPC functions in C57BL/6J mice via the PI3K/AKT/eNOS pathways, partially restoring TNF-α-induced EPC dysfunction ( Nana et al, 2015 ).…”

Dyslipidemia Part 1—Review of Lipid Metabolism and Vascular Cell Physiology

“…Prior studies showed that HDL activation of eNOS is receptor SR-B1 dependent. 81 Endothelial nitric oxide synthase is also enhanced by administering peptides that mimic HDL protein apoA1, such as L4F and D4F. 81,82 Recent studies have shown that eNOS activation requires the concurrent activation of the S1P receptor, S1PR3.…”

“…81 Endothelial nitric oxide synthase is also enhanced by administering peptides that mimic HDL protein apoA1, such as L4F and D4F. 81,82 Recent studies have shown that eNOS activation requires the concurrent activation of the S1P receptor, S1PR3. 69 Sphingosine-1-phosphate is a lysophospholipid found in HDL particles and has been implicated as an important component of HDL that confers its atheroprotective properties, as experiments using S1P-deficient HDLs showed decreased eNOS activation, despite increased eNOS production.…”

Drinking Molecular Hydrogen Water Is Beneficial to Cardiovascular Function in Diet-Induced Obesity Mice

“…Previous studies have reported the dysfunction of BM-derived EPCs in MetS in both humans and mice [ 16 , 49 , 50 ].…”