Ischemic-Trained Monocytes Improve Arteriogenesis in a Mouse Model of Hindlimb Ischemia.
Ischemic-Trained Monocytes Improve Arteriogenesis in a Mouse Model of Hindlimb Ischemia.
复制标题
DOI：
10.1161/atvbaha.121.317197
复制
发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Lassance-Soares RM
中科院分区：
文献类型：
--
作者：
Falero-Diaz G;Barboza CA;Pires F;Fanchin M;Ling J;Zigmond ZM;Griswold AJ;Martinez L;Vazquez-Padron RI;Velazquez OC;Lassance-Soares RM
单核细胞在动脉形成中起着重要作用，它可以通过功能重编程来建立免疫记忆，从而改变它们对第二次挑战的反应。这个过程被称为“训练免疫”，是由改变单核细胞代谢的损伤引起的，增加了缺氧诱导因子(HIF)-1α水平。由于缺血增强了HIF-1α，我们评估了缺血是否会导致单核细胞的功能性重编程，这将有助于后肢缺血后的动脉生成。经24小时股动脉（FA）闭塞（训练24小时）或假手术缺血处理的小鼠，1周后进行后肢缺血；24h训练小鼠后肢缺血后血流恢复和动脉生成明显改善。采用24小时训练或假供体小鼠骨髓来源单核细胞（BM-Mono）过继移植，发现后肢缺血受体接受24小时缺血训练的单核细胞后，血流恢复和动脉生成显著。此外，缺血训练的脑单核细胞在FA闭塞期间增加了HIF-1α和GLUT-1基因的表达。循环细胞因子和GLUT-1在FA闭塞时也上调。对缺血训练单核细胞和假性脑缺血单核细胞进行的转录组学分析和验证性qPCR显示，在缺血训练单核细胞中，15个差异表达最高的基因中有4个与脂质代谢有关。脂质组学分析证实，缺血训练改变了这些单核细胞的胆固醇代谢。此外，暴露于缺氧24小时的小鼠BM-Mono中，qPCR检测到的几种组蛋白修饰表观遗传酶发生了改变。脑缺血训练导致独特的基因谱，并改善后肢缺血后的血流和动脉生成。
Monocytes, which play an important role in arteriogenesis, can build immunological memory by a functional reprogramming that modifies their response to a second challenge. This process, called “trained immunity,” is evoked by insults that shift monocyte metabolism, increasing hypoxia-inducible factor (HIF)-1α levels. Since ischemia enhances HIF-1α, we evaluate whether ischemia can lead to a functional reprogramming of monocytes, which would contribute to arteriogenesis after hindlimb ischemia. Mice exposed to ischemia by 24h of femoral artery (FA) occlusion (24h trained) or sham were subjected to hindlimb ischemia one week later; the 24h trained mice showed significant improvement in blood flow recovery and arteriogenesis after hindlimb ischemia. Adoptive transfer using bone marrow-derived monocytes (BM-Mono) from 24h trained or sham donor mice, demonstrated that recipients subjected to hindlimb ischemia who received 24h ischemic-trained monocytes had remarkable blood flow recovery and arteriogenesis. Further, ischemic-trained BM-Mono had increased HIF-1α and GLUT-1 gene expression during FA occlusion. Circulating cytokines and GLUT-1 were also up-regulated during FA occlusion.Transcriptomic analysis and confirmatory qPCR performed in 24h trained and sham BM-Mono revealed that among the 15 top differentially expressed genes, four were involved in lipid metabolism in the ischemic-trained monocytes. Lipidomic analysis confirmed that ischemia training altered the cholesterol metabolism of these monocytes. Further, several histone-modifying epigenetic enzymes measured by qPCR were altered in mouse BM-Mono exposed to 24h hypoxia. Ischemia training in BM-Mono leads to a unique gene profile and improves blood flow and arteriogenesis after hindlimb ischemia.
影响因子：
5.2
作者：
Urao, Norifumi;McKinney, Ronald D.;Fukai, Tohru;Ushio-Fukai, Masuko
通讯作者：
Ushio-Fukai, Masuko