Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, Worcester, MA.
J Am Heart Assoc. 2014 Jan 27;3(1):e000241. doi: 10.1161/JAHA.113.000241.
Clinical studies suggest that hypercholesterolemia may cause ageing in hematopoietic stem cells (HSCs) because ageing-associated alterations were found in peripheral blood cells and their bone marrow residing precursors in patients with advanced atherosclerosis. We hypothesized that hypercholesterolemia induces oxidant stress in hematopoietic stems cells that accelerates their ageing.
Here we show that HSCs from ApoE(-/-) mice, as well as HSCs from C57Bl/6 mice fed a high cholesterol diet (HCD) accumulated oxLDL and had greater ROS levels. In accordance, the expression pattern of the genes involved in ROS metabolism changed significantly in HSCs from ApoE(-/-) mice. Hypercholesterolemia caused a significant reduction in phenotypically defined long-term HSC compartment, telomere length, and repopulation capacity of KTLS cells, indicating accelerated ageing in these cells. Gene array analysis suggested abnormal cell cycle status, and the key cell cycle regulators including p19(ARF), p27(Kip1) and p21(Waf1) were upregulated in KTLS cells from hypercholesterolemic mice. These effects were p38-dependent and reversed in vivo by treatment of hypercholesterolemic mice with antioxidant N-acetylcysteine. The oxidant stress also caused aberrant expression of Notch1 that caused loss of quiescence and proliferation leading to the expansion of KTLS compartment in hypercholesterolemic mice.
Taken together, we provide evidence that hypercholesterolemia can cause oxidant stress that accelerates the ageing and impairs the reconstitution capacity of HSCs.
临床研究表明，高胆固醇血症可能导致造血干细胞（HSCs）衰老，因为在患有晚期动脉粥样硬化的患者的外周血细胞及其骨髓驻留前体细胞中发现了与衰老相关的改变。我们假设高胆固醇血症会在造血干细胞中引起氧化应激，从而加速其衰老。
在这里，我们表明，ApoE（-/-）小鼠的 HSCs 以及用高胆固醇饮食（HCD）喂养的 C57Bl/6 小鼠的 HSCs 会积累 oxLDL 并具有更高的 ROS 水平。相应地，参与 ROS 代谢的基因的表达模式在 ApoE（-/-）小鼠的 HSCs 中发生了显著变化。高胆固醇血症导致表型定义的长期 HSC 隔室、端粒长度和 KTLS 细胞的再群体能力显著减少，表明这些细胞加速衰老。基因阵列分析表明细胞周期状态异常，关键细胞周期调节剂包括 p19（ARF）、p27（Kip1）和 p21（Waf1）在高胆固醇血症小鼠的 KTLS 细胞中上调。这些效应依赖于 p38，并且在体内通过用抗氧化剂 N-乙酰半胱氨酸治疗高胆固醇血症小鼠而得到逆转。氧化应激还导致 Notch1 的异常表达，导致静止和增殖的丧失，从而导致高胆固醇血症小鼠的 KTLS 隔室扩张。
综上所述，我们提供的证据表明，高胆固醇血症可引起氧化应激，从而加速 HSCs 的衰老并损害其重建能力。
