Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Radiology, National Postgraduate Medical College of Nigeria, Lagos, Nigeria.
J Cell Physiol. 2024 Nov;239(11):e31415. doi: 10.1002/jcp.31415. Epub 2024 Sep 12.
Chronic systemic inflammation significantly increases myocardial infarction risk in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis, contributing to cardiovascular disease. We aimed to characterize endothelial cell (EC) chemokines, cytokine, and chemokine receptors of PLWH, hypothesizing that in our cohort, glucose intolerance contributes to their differential expression implicated in endothelial dysfunction. Using single-cell transcriptomic analysis, we phenotyped chemokine and cytokine receptor expression on arterial ECs, capillary ECs, venous ECs, and vascular smooth muscle cells (VSMCs) in subcutaneous adipose tissue of 59 PLWH with and without glucose intolerance. Our results show that arterial and capillary ECs express significantly higher interferon and tumor necrosis factor (TNF) receptors than venous ECs and VSMCs. Venous ECs exhibited more interleukin (IL)1R1 and ACKR1 receptors, and VSMCs showed significant IL6R expression than arterial and capillary ECs. When stratified by group, arterial ECs from PLWH with glucose intolerance expressed significantly higher IL1R1, IL6R, CXCL12, CCL14, and ICAM2 transcripts than arterial ECs from PLWH without diabetes. Of the different vascular cell types studied, arterial ECs as a proportion of all ECs in adipose tissue were positively correlated with plasma fasting blood glucose. In contrast, venous ECs and VSMCs were positively correlated with plasma IL6. To directly assess the effect of plasma from PLWH on endothelial function, we cultured human arterial ECs (HAECs) in plasma-conditioned media from PLWH and performed bulk RNA sequencing. Plasma from PLWH stimulated ECs with the upregulation of genes that enrich for the oxidative phosphorylation and the TNF-α via NFK-β pathways. In conclusion, ECs in PLWH show heterogeneous cytokine and chemokine receptor expression, and arterial ECs were the most influenced by glucose intolerance. Further research must explicate cytokine and chemokine roles in EC dysfunction and identify biomarkers for disease progression and therapeutic response.
慢性系统性炎症显著增加了 HIV 感染者（PLWH）的心肌梗死风险。内皮细胞功能障碍破坏了血管稳态调节，增加了血管收缩、炎症和血栓形成的风险，从而导致心血管疾病。我们旨在描述 PLWH 的内皮细胞（EC）趋化因子、细胞因子和趋化因子受体，假设在我们的队列中，葡萄糖耐量异常导致了与内皮功能障碍相关的差异表达。使用单细胞转录组分析，我们对皮下脂肪组织中的动脉 ECs、毛细血管 ECs、静脉 ECs 和血管平滑肌细胞（VSMCs）进行了表型分析，这些 ECs 来自 59 名有或没有葡萄糖耐量异常的 PLWH。我们的研究结果表明，动脉和毛细血管 ECs 表达的干扰素和肿瘤坏死因子（TNF）受体明显高于静脉 ECs 和 VSMCs。静脉 ECs 表现出更高的白细胞介素（IL）1R1 和 ACKR1 受体，而 VSMCs 表达的 IL6R 明显高于动脉和毛细血管 ECs。按组分层时，葡萄糖耐量异常的 PLWH 的动脉 ECs 表达的 IL1R1、IL6R、CXCL12、CCL14 和 ICAM2 转录本明显高于没有糖尿病的 PLWH 的动脉 ECs。在研究的不同血管细胞类型中，脂肪组织中动脉 ECs 占所有 ECs 的比例与血浆空腹血糖呈正相关。相比之下，静脉 ECs 和 VSMCs 与血浆 IL6 呈正相关。为了直接评估 PLWH 血浆对内皮功能的影响，我们在 PLWH 的血浆条件培养基中培养人动脉 ECs（HAECs），并进行 bulk RNA 测序。PLWH 的血浆刺激 ECs 上调了与氧化磷酸化和 TNF-α 途径的 NFK-β 相关的基因。总之，PLWH 的 ECs 表现出异质的细胞因子和趋化因子受体表达，而动脉 ECs 受葡萄糖耐量异常的影响最大。进一步的研究必须阐明细胞因子和趋化因子在 EC 功能障碍中的作用，并确定用于疾病进展和治疗反应的生物标志物。
