Hamo Carine E, Schlamp Florencia, Drenkova Kamelia, Jindal Manila, Fadzan Maja, Akinlonu Adedoyin, Goldberg Ira, Garshick Michael S, Berger Jeffrey S
Department of Medicine, Center for the Prevention of Cardiovascular Disease, New York University School of Medicine, New York City, NY; Leon H. Charney Division of Cardiology, Department of Medicine, Cardiovascular Research Center, New York University School of Medicine, New York City, NY.
Leon H. Charney Division of Cardiology, Department of Medicine, Cardiovascular Research Center, New York University School of Medicine, New York City, NY.
Am Heart J. 2024 Mar;269:201-204. doi: 10.1016/j.ahj.2023.11.004. Epub 2024 Jan 5.
Cardiometabolic risk factors diabetes, obesity, and hypertension are highly prevalent and contribute to increased cardiovascular disease (CVD). Endothelial dysfunction precedes CVD development. The current study aimed to investigate the EC transcriptome among individuals with varying degree of cardiometabolic risk.
Adult participants without CVD and various degrees of cardiometabolic risk factor burden (hypertension, diabetes, obesity) were included. Participants underwent brachial vein EC harvesting followed by RNA sequencing. To evaluate the association between cardiometabolic comorbidity burden and outcome transcripts we performed linear regression with multivariable models, adjusting for age, sex, and race/ethnicity.
A total of 18 individuals were included in the present analysis (mean age 47 ± 14, 44% female, and 61% White adults). Endothelial cell RNA sequencing revealed 588 differentially expressed transcripts (p-adj <0.05) with excellent discrimination in unsupervised hierarchical clustering analysis. Gene ontology enrichment analysis revealed upregulated pathways associated with T-cell activation (NES = 2.22, p<0.001), leukocyte differentiation (NES= 2.16, p<0.001), leukocyte migration (NES= 2.12, p<0.001), regulation of cell-cell adhesion (NES= 1.91, p=0.006). Downregulated pathways of interest included endothelial cell proliferation (NES= -1.68, p=0.03) and response to interleukin-1 (NES= -1.61, p=0.04). Upregulated genes included VCAM1, CEACAM1, ADAM 17, and CD99L2, all with a log-2-fold change >3 and p-adj <0.05. These genes demonstrated a graded increase in mean normalized counts with increasing number of risk factors.
We demonstrate a proinflammatory and pro-adhesive EC transcriptome associated with increased cardiometabolic risk factor burden offering insight into a potential mechanism linking these risk factors with the development of CVD.
心脏代谢危险因素，如糖尿病、肥胖和高血压极为常见，会增加心血管疾病（CVD）的发病风险。内皮功能障碍先于心血管疾病的发生。本研究旨在调查不同程度心脏代谢风险个体的内皮细胞转录组。
纳入无心血管疾病且有不同程度心脏代谢危险因素负担（高血压、糖尿病、肥胖）的成年参与者。参与者接受肱静脉内皮细胞采集，随后进行RNA测序。为评估心脏代谢合并症负担与结果转录本之间的关联，我们采用多变量模型进行线性回归，并对年龄、性别和种族/民族进行了校正。
本分析共纳入18名个体（平均年龄47±14岁，44%为女性，61%为白人成年人）。内皮细胞RNA测序显示588个差异表达转录本（p值校正<0.05），在无监督层次聚类分析中具有良好的区分度。基因本体富集分析显示与T细胞活化相关的上调通路（标准化富集分数[NES]=2.22，p<0.001）、白细胞分化（NES=2.16，p<0.001）、白细胞迁移（NES=2.12，p<0.001）、细胞间粘附调节（NES=1.91，p=0.006）。感兴趣的下调通路包括内皮细胞增殖（NES=-1.68，p=0.03）和对白介素-1的反应（NES=-1.61，p=0.04）。上调基因包括血管细胞粘附分子-1（VCAM1）、癌胚抗原相关细胞粘附分子1（CEACAM1）、解聚素金属蛋白酶17（ADAM 17）和CD99样蛋白2（CD99L2），所有基因的log2倍变化均>3且p值校正<0.05。这些基因的平均标准化计数随危险因素数量的增加呈分级增加。
我们证明了一种与心脏代谢危险因素负担增加相关的促炎和促粘附内皮细胞转录组，为将这些危险因素与心血管疾病发展联系起来的潜在机制提供了见解。
