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.
Highlights
Diet has been shown to play an important role in the development of cardiovascular disease, which remains the major cause of death in western countries [1]
In this study, we assessed the effect of Rev-D4F on the number of different cell populations in the peripheral blood such as endothelial progenitor cells (EPCs), lymphocytes, neutrophils, and monocytes, the inflammation of the arterial wall induced by a high fat diet, and the improvement of EPC functions impaired by the inflammatory factor tumor necrosis factor-α (TNF-α) through the PI3K/AKT pathway
Analysis of thoracic aortic sections showed that the high fat diet significantly decreased the number of EPCs (c-kit+) (Fig 2C and 2E), whereas Rev-D4F obviously increased the number of c-kit+ EPCs to restore impaired aortic endothelium induced by the high fat diet (Fig 2E)
Summary
Diet has been shown to play an important role in the development of cardiovascular disease, which remains the major cause of death in western countries [1]. It has been shown that a high fat diet contributes to the impairment of vascular function both in healthy subjects and in patients with cardiovascular disease (CVD) [7], as well as the reduction of the circulating levels of EPCs after critical limb ischemia [8] and the increase of the level of leukocytes in the peripheral blood [9] Based on those observations, we speculated that a high fat diet induced peripheral blood micro environment changes (such as changes in the level of total cholesterol [TC], nitric oxide [NO], stromal cell derived factor 1α [SDF-1α], vascular endothelial growth factor [VEGF], tumor necrosis factor [TNF]-α, etc.), indirectly influencing endothelial repair through mobilization of bone marrow cell and peripheral blood progenitor cell transdifferentiation. In this study, we assessed the effect of Rev-D4F on the number of different cell populations in the peripheral blood such as EPCs, lymphocytes, neutrophils, and monocytes, the inflammation of the arterial wall induced by a high fat diet, and the improvement of EPC functions impaired by the inflammatory factor TNF-α through the PI3K/AKT pathway
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