Centers for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Department of Clinical Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
Redox Biol. 2019 Jun;24:101221. doi: 10.1016/j.redox.2019.101221. Epub 2019 May 22.
To test our hypothesis that proatherogenic lysophosphatidylcholine (LPC) upregulates trained immunity pathways (TIPs) in human aortic endothelial cells (HAECs), we conducted an intensive analyses on our RNA-Seq data and histone 3 lysine 14 acetylation (H3K14ac)-CHIP-Seq data, both performed on HAEC treated with LPC. Our analysis revealed that: 1) LPC induces upregulation of three TIPs including glycolysis enzymes (GE), mevalonate enzymes (ME), and acetyl-CoA generating enzymes (ACE); 2) LPC induces upregulation of 29% of 31 histone acetyltransferases, three of which acetylate H3K14; 3) LPC induces H3K14 acetylation (H3K14ac) in the genomic DNA that encodes LPC-induced TIP genes (79%) in comparison to that of in LPC-induced effector genes (43%) including ICAM-1; 4) TIP pathways are significantly different from that of EC activation effectors including adhesion molecule ICAM-1; 5) reactive oxygen species generating enzyme NOX2 deficiency decreases, but antioxidant transcription factor Nrf2 deficiency increases, the expressions of a few TIP genes and EC activation effector genes; and 6) LPC induced TIP genes(81%) favor inter-chromosomal long-range interactions (CLRI, trans-chromatin interaction) while LPC induced effector genes (65%) favor intra-chromosomal CLRIs (cis-chromatin interaction). Our findings demonstrated that proatherogenic lipids upregulate TIPs in HAECs, which are a new category of qualification markers for chronic disease risk factors and conditional DAMPs and potential mechanisms for acute inflammation transition to chronic ones. These novel insights may lead to identifications of new cardiovascular risk factors in upregulating TIPs in cardiovascular cells and novel therapeutic targets for the treatment of metabolic cardiovascular diseases, inflammation, and cancers. (total words: 245).
为了验证我们的假设，即致动脉粥样硬化的溶血磷脂酰胆碱（LPC）上调人主动脉内皮细胞（HAEC）中的训练免疫途径（TIPs），我们对 LPC 处理后的 HAEC 的 RNA-Seq 数据和组蛋白 3 赖氨酸 14 乙酰化（H3K14ac）-CHIP-Seq 数据进行了深入分析。我们的分析表明：1）LPC 诱导三种 TIPs 的上调，包括糖酵解酶（GE）、甲羟戊酸途径酶（ME）和乙酰辅酶 A 生成酶（ACE）；2）LPC 诱导 31 种组蛋白乙酰转移酶中的 29%上调，其中 3 种能够乙酰化 H3K14；3）与 LPC 诱导的效应基因（43%）相比，LPC 诱导 TIP 基因（79%）的基因组 DNA 中 H3K14 发生乙酰化（H3K14ac），包括 ICAM-1；4）TIP 途径与 EC 激活效应物途径明显不同，包括粘附分子 ICAM-1；5）活性氧生成酶 NOX2 缺乏会降低，但抗氧化转录因子 Nrf2 缺乏会增加少数 TIP 基因和 EC 激活效应基因的表达；6）LPC 诱导的 TIP 基因（81%）有利于染色体间的长距离相互作用（CLRI，染色质间相互作用），而 LPC 诱导的效应基因（65%）有利于染色体内的 CLRI（染色质内相互作用）。我们的研究结果表明，致动脉粥样硬化的脂质会在上皮细胞中上调 TIPs，这是慢性疾病危险因素和条件 DAMPs 的一类新的定性标志物，也是急性炎症向慢性炎症转化的潜在机制。这些新的见解可能会导致在心血管细胞中上调 TIPs 时发现新的心血管危险因素，并为代谢性心血管疾病、炎症和癌症的治疗提供新的治疗靶点。（总字数：245）
