Human ApoA-I Transfer Attenuates Transplant Arteriosclerosis via Enhanced Incorporation of Bone marrow–derived Endothelial Progenitor Cells

Abstract

Objective— Transplant arteriosclerosis is the leading cause of graft failure and death in patients with heart transplantation. Endothelial progenitor cells (EPCs) contribute to endothelial regeneration in allografts. We investigated whether increased HDL cholesterol induced by adenoviral human apoA-I (AdA-I) transfer increases number and function of EPCs, promotes incorporation of EPCs in Balb/c allografts transplanted paratopically in C57BL/6 ApoE −/− mice, and attenuates transplant arteriosclerosis. Methods and Results— EPC number in ApoE −/− mice was increased after AdA-I transfer as evidenced by 1.5-fold ( P <0.01) higher Flk-1 Sca-1–positive cells and 1.4-fold ( P <0.01) higher DiI-acLDL isolectin-positive spleen cells. In addition, HDL enhanced EPC function in vitro. Incorporation of bone marrow–derived EPCs was 5.8-fold ( P <0.01) higher at day 21 after transplantation in AdA-I-treated apoE −/− mice compared with control mice. Enhanced endothelial regeneration in AdA-I-treated apoE −/− mice as evidenced by a 2.6-fold ( P <0.01) increase of CD31-positive endothelial cells resulted in a 1.4-fold ( P =0.059) reduction of neointima and a 3.9-fold ( P <0.01) increase of luminal area. Conclusion— Human apoA-I transfer increases the number of circulating EPCs, enhances their incorporation into allografts, promotes endothelial regeneration, and attenuates neointima formation in a murine model of transplant arteriosclerosis.

Reduction of both number and proliferative activity of human endothelial progenitor cells in obesity

“…The same relates to decreased concentrations of plasma HDL and of its associated ApoA1, both of which are commonly linked to atherogenic dyslipidemia in obesity 21 and are now shown to be associated with fewer numbers of EPCs. Although there are only limited and controversial data on the association of HDL and circulating EPCs, 12,14,16,22 human ApoA1 gene transfer has already been shown to increase EPCs in bone marrow and in the circulation of mice, 23 thereby confirming the results of our study.…”

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

“…However, there are very significant methodological challenges to detect incorporation of circulating progenitor cells in the endothelium (Hagensen et al 2010). Incorporation of EPCs is in general a relatively rare event (Feng et al 2008(Feng et al , 2009aHagensen et al 2010). High-resolution multichannel sequential confocal scanning microscopy provides a platform for colocalisation analysis with high specificity, which is required in lege artis cell tracking studies (De Geest 2009).…”

“…HDLs enhance EPC-mediated repair (Feng et al 2008(Feng et al , 2009aTso et al 2006). The effect of HDL on EPC number, function, and incorporation occurs via SR-BI (Feng et al 2009b).…”

“…Hu et al (2003) have demonstrated that EPCs contribute to endothelial regeneration in murine allografts. Moreover, increased HDL induced by hepatocyte-directed human apo A-I gene transfer in C57BL/6 apo E À/À mice enhanced the incorporation of bone marrow-derived EPCs into the injured endothelium of allografts from donor BALB/c mice and reduced neointima formation in these allografts (Feng et al 2008). In subsequent experiments using BALB/c allografts in wild-type C57BL/6 mice, it was demonstrated that increased EPC incorporation and attenuation of allograft vasculopathy induced by hepatocytedirected human apo A-I gene transfer are strictly dependent on SR-BI expression in bone marrow and bone marrow-derived cells.…”

Apolipoprotein A-I and lecithin:cholesterol acyltransferase transfer induce cholesterol unloading in complex atherosclerotic lesions

“…The E1E3E4-deleted control vector Adnull 46 does not contain an expression cassette whereas the E1E3E4-deleted vectors AdrA-I and AdrLCAT induce hepatocyte-specific expression of rabbit apo A-I and rabbit LCAT, respectively. To increase the diameter of sinusoidal fenestrae, intraportal injection of sodium decanoate (Sigma-Aldrich, Steinheim, Germany) at a dose of 0.3 mmol kg À1 was performed 10 min before intraportal gene transfer of 4 Â 10 12 adenoviral particles …”