Bone marrow-derived endothelial progenitor cells (EPCs) contribute to endothelial repair and angiogenesis. Reduced number of circulating EPCs is associated with future cardiovascular events. We tested whether dysregulated glucose and/or triglyceride (TG) metabolism has an impact on EPC homeostasis. The analysis of metabolic factors associated with circulating EPC number in humans revealed that postprandial hyperglycemia is negatively correlated with circulating EPC number and this correlation appears to be further enhanced in the presence of postprandial hypertriglyceridemia (hTG). We therefore examined the effect of glucose/TG spikes on bone marrow lineage-sca-1+c-kit+ (LSK) cells in mice, because primitive EPCs reside in bone marrow LSK fraction.Repetitive glucose+lipid (GL) spikes, but not glucose (G) or lipid (L) spikes alone, induced senescence-like phenotypes of LSK cells, and this phenomenon was reversible after cessation of GL spikes. G spikes and GL spikes differentially affected transcriptional program of LSK cell metabolism and differentiation. GL spikes upregulated a histone H3K27 demethylase JMJD3, and inhibition of JMJD3 eliminated GL spikes-induced LSK cell senescence-like phenotypes. These observations suggest that postprandial glucose/TG dysmetabolism modulate transcriptional regulation in LSK cells through H3K27 demethylase-mediated epigenetic regulation, leading to senescence-like phenotypes of LSK cells, reduced number of circulating EPCs, and development of atherosclerotic cardiovascular disease.

中文翻译：

---

葡萄糖和脂质的重复峰值通过 H3K27me3 去甲基化酶介导的表观遗传调控诱导骨髓干细胞的衰老样表型

骨髓来源的内皮祖细胞 (EPC) 有助于内皮修复和血管生成。循环 EPC 数量减少与未来的心血管事件有关。我们测试了失调的葡萄糖和/或甘油三酯 (TG) 代谢是否对 EPC 稳态产生影响。与人体循环 EPC 数量相关的代谢因素分析表明，餐后高血糖与循环 EPC 数量呈负相关，并且在存在餐后高甘油三酯血症 (hTG) 的情况下，这种相关性似乎进一步增强。因此，我们检查了葡萄糖/TG 尖峰对小鼠骨髓谱系-sca-1+c-kit+ (LSK) 细胞的影响，因为原始 EPC 存在于骨髓 LSK 部分。重复的葡萄糖 + 脂质 (GL) 尖峰，但不是单独的葡萄糖 (G) 或脂质 (L) 峰值，诱导 LSK 细胞的衰老样表型，这种现象在 GL 尖峰停止后是可逆的。G 尖峰和 GL 尖峰不同地影响 LSK 细胞代谢和分化的转录程序。GL 尖峰上调了组蛋白 H3K27 去甲基化酶 JMJD3，抑制 JMJD3 消除了 GL 尖峰诱导的 LSK 细胞衰老样表型。这些观察结果表明，餐后葡萄糖/TG 代谢障碍通过 H3K27 脱甲基酶介导的表观遗传调节调节 LSK 细胞的转录调节，导致 LSK 细胞的衰老样表型、循环 EPC 数量减少和动脉粥样硬化心血管疾病的发展。G 尖峰和 GL 尖峰不同地影响 LSK 细胞代谢和分化的转录程序。GL 尖峰上调了组蛋白 H3K27 去甲基化酶 JMJD3，抑制 JMJD3 消除了 GL 尖峰诱导的 LSK 细胞衰老样表型。这些观察结果表明，餐后葡萄糖/TG 代谢障碍通过 H3K27 脱甲基酶介导的表观遗传调节调节 LSK 细胞的转录调节，导致 LSK 细胞的衰老样表型、循环 EPC 数量减少和动脉粥样硬化心血管疾病的发展。G 尖峰和 GL 尖峰不同地影响 LSK 细胞代谢和分化的转录程序。GL 尖峰上调了组蛋白 H3K27 去甲基化酶 JMJD3，抑制 JMJD3 消除了 GL 尖峰诱导的 LSK 细胞衰老样表型。这些观察结果表明，餐后葡萄糖/TG 代谢障碍通过 H3K27 脱甲基酶介导的表观遗传调节调节 LSK 细胞的转录调节，导致 LSK 细胞的衰老样表型、循环 EPC 数量减少和动脉粥样硬化心血管疾病的发展。