Elucidation of accelerated atherosclerosis in cardiac transplantation

在心脏移植患者中观察到的动脉粥样硬化加速是移植物存活的主要限制因素，并将严重导致供者短缺。免疫机制被认为与这一机制密切相关。不同品系的近交系小鼠对动脉粥样硬化的易感性不同。SJL/J小鼠动脉粥样硬化抵抗，B10S小鼠动脉粥样硬化易感。这种差异归因于未知的ATH 7等位基因，与血清高密度脂蛋白(HDL)水平无关，提示ATH 7可能位于血细胞中。为了探讨骨髓来源细胞在动脉粥样硬化形成中的作用，我们制备了受照射的BM嵌合体，受者apo E-/-小鼠与SJL/J或B10S BM细胞和同基因apo E-/-BM细胞重组。移植载脂蛋白E-/-BM细胞建立混合嵌合体，使免疫活性细胞具有稳定的耐受性。在两种嵌合体中均可观察到动脉粥样硬化病变的明显减少，这可能与SJL/J或B10S来源的BM来源的细胞增加脂蛋白清除有关。然而，由于接受动脉粥样硬化抵抗的SJL/J BM细胞的载脂蛋白E/-受体的血清非高密度脂蛋白水平高于接受易感B10S BM细胞的患者，因此SJL/J的BM来源细胞对脂质的吸收效率较低。这些结果表明，骨髓来源细胞摄取脂质的效率是SJL/J株关节硬化性病变的关键决定因素。这项研究的结果将有助于开发新的策略来减少心脏移植患者观察到的加速的动脉粥样硬化，并有助于显著改善供体短缺的状况。

Accelerated atherosclerosis observed in cardiac transplantation patients is a major limiting factor for graft survival, and will seriously contribute to the shortage of donors. Immune mechanism is considered to be strongly involved in this mechanism. Atherosclerosis susceptibility differs among inbred mouse strains fed an atherogenic diet. SJL/J mice are atherosclerosis resistant and B10S mice are atherosclerosis susceptible. This difference is attributed to unidentified Ath 7 allele independent of serum high-density lipoprotein (HDL) levels, suggesting that Ath 7 might be located in blood cells. To examine the roles of bone marrow (BM) derived cells in the development of atherosclerosis, we prepared irradiation BM chimeras where irradiated recipients, apo E-/- mice, were reconstituted with SJL/J or B10S BM cells plus syngeneic apo E-/- BM cells. The apo E-/- BM cells were transplanted to establish mixed chimerism, which resulted in stable tolerance in the immunocompetent cells. In both chimeras marked reductions of aortic atherosclerotic lesions were observed, which might be attributed to the increase in lipoprotein clearance by BM derived cells from SJL/J or B10S. However, since serum non-HDL levels was higher in apo E-/- recipients given atherosclerotsis resistant SJL/J BM cells than those given susceptible B10S BM cells, BM derived cells of SJL/J were considered to take lipids less efficiently. These results suggest that efficiency of lipid uptake by BM derived cells is a key determinant of athrosclerosis lesion in SJL/J strain. The results obtained in this study will significantly contribute to the development of new strategies to reduce the accelerated atherosclerosis observed in cardiac transplantation patients, and help to markedly improve the situation of donor shortage.