Department of Medicine II, Kansai Medical University, Osaka, Japan.
Department of Pediatrics, Kansai Medical University, Osaka, Japan.
Am J Physiol Heart Circ Physiol. 2021 Nov 1;321(5):H920-H932. doi: 10.1152/ajpheart.00261.2021. Epub 2021 Sep 17.
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. Combination of hyperglycemia and hypertriglyceridemia is associated with increased risk of atherosclerotic cardiovascular disease. We found that ) hypertriglyceridemia may enhance the negative impact of hyperglycemia on circulating EPC number in humans and ) metabolic stress induced by glucose + triglyceride spikes in mice results in senescence-like phenotypes of bone marrow stem/progenitor cells via H3K27me3 demethylase-mediated epigenetic regulation. These findings have important implications for understanding the pathogenesis of atherosclerotic cardiovascular disease in patients with T2DM.
骨髓来源的内皮祖细胞 (EPCs) 有助于内皮修复和血管生成。循环 EPC 数量减少与未来心血管事件有关。我们测试了葡萄糖和/或甘油三酯 (TG) 代谢失调是否对 EPC 稳态有影响。分析与人类循环 EPC 数量相关的代谢因素表明，餐后高血糖与循环 EPC 数量呈负相关，而这种相关性在餐后高甘油三酯血症 (hTG) 存在时似乎进一步增强。因此，我们在小鼠中检查了葡萄糖/TG 波动对骨髓谱系 -sca-1 c-kit (LSK) 细胞的影响，因为原始 EPC 存在于骨髓 LSK 细胞群中。重复的葡萄糖+脂质 (GL) 波动，但不是单独的葡萄糖 (G) 或脂质 (L) 波动，诱导了 LSK 细胞的衰老样表型，并且这种现象在 GL 波动停止后是可逆的。G 波动和 GL 波动对 LSK 细胞代谢和分化的转录程序有不同的影响。GL 波动上调了组蛋白 H3K27 去甲基化酶 JMJD3，并且抑制 JMJD3 消除了 GL 波动诱导的 LSK 细胞衰老样表型。这些观察结果表明，餐后葡萄糖/TG 代谢失调通过 H3K27 去甲基化酶介导的表观遗传调控调节 LSK 细胞中的转录调节，导致 LSK 细胞衰老样表型、循环 EPC 数量减少和动脉粥样硬化性心血管疾病的发展。高血糖和高甘油三酯血症的结合与动脉粥样硬化性心血管疾病风险的增加有关。我们发现，) 高甘油三酯血症可能增强高血糖对人类循环 EPC 数量的负面影响，以及) 葡萄糖+甘油三酯波动在小鼠中引起的代谢应激通过 H3K27me3 去甲基化酶介导的表观遗传调控导致骨髓干细胞/祖细胞的衰老样表型。这些发现对于理解 T2DM 患者动脉粥样硬化性心血管疾病的发病机制具有重要意义。
