Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Germany (J.M.K., I.A.G., M.W., S.E., T.M., M.N.M.-W., A.K., K.E.K., V.F., S.G., U.L., J.-N.B.).
Central German Heart Alliance (J.M.K., I.A.G., M.W., S.E., T.M., M.N.M.-W., A.K., K.E.K., V.F., S.G., H.T., U.L., J.-N.B.).
Circulation. 2024 Oct;150(14):1101-1120. doi: 10.1161/CIRCULATIONAHA.124.069315. Epub 2024 Jul 15.
Activation of the immune system contributes to cardiovascular diseases. The role of human-specific long noncoding RNAs in cardioimmunology is poorly understood.
Single-cell sequencing in peripheral blood mononuclear cells revealed a novel human-specific long noncoding RNA called (heart failure-associated transcript 4). expression was assessed in several in vitro and ex vivo models of immune cell activation, as well as in the blood of patients with heart failure (HF), acute myocardial infarction, or cardiogenic shock. The transcriptional regulation of was verified through cytokine treatment and single-cell sequencing. Loss-of-function and gain-of-function studies and multiple RNA-protein interaction assays uncovered a mechanistic role of in the monocyte anti-inflammatory gene program. expression and function was characterized in a vascular injury model in NOD.CB17-Prkdc scid/Rj mice.
expression was increased in the blood of patients with HF, acute myocardial infarction, or cardiogenic shock. levels distinguished patients with HF from people without HF and predicted all-cause mortality in a cohort of patients with HF over 7 years of follow-up. Monocytes, particularly anti-inflammatory CD16 monocytes, which are increased in patients with HF, are the primary source of expression in the blood. is transcriptionally activated by treatment with anti-inflammatory interleukin-10. activates anti-inflammatory and inhibits proinflammatory gene expression. Increased levels result in a shift toward more CD16 monocytes. binds to S100A9, causing a monocyte subtype switch, thereby reducing inflammation. As a result, improves endothelial barrier integrity during inflammation and promotes vascular healing after injury in mice.
These results characterize a novel endogenous anti-inflammatory pathway that involves the conversion of monocyte subtypes into anti-inflammatory CD16 monocytes. The data identify a novel function for the class of long noncoding RNAs by preventing protein secretion and suggest long noncoding RNAs as potential targets for interventions in the field of cardioimmunology.
免疫系统的激活会导致心血管疾病。人类特异性长非编码 RNA 在心脏免疫学中的作用尚未被充分了解。
对外周血单核细胞进行单细胞测序，揭示了一种新型的人类特异性长非编码 RNA，称为 （心力衰竭相关转录物 4）。在几种体外和离体免疫细胞激活模型中以及心力衰竭 (HF)、急性心肌梗死或心源性休克患者的血液中评估了 的表达。通过细胞因子处理和单细胞测序验证了 的转录调控。通过功能丧失和获得功能研究以及多种 RNA-蛋白相互作用检测，揭示了 在单核细胞抗炎基因程序中的作用机制。在 NOD.CB17-Prkdc scid/Rj 小鼠的血管损伤模型中对 表达和功能进行了表征。
HF、急性心肌梗死或心源性休克患者的血液中 表达增加。水平可将 HF 患者与无 HF 患者区分开来，并在 HF 患者的队列中预测 7 年以上的全因死亡率。单核细胞，特别是在 HF 患者中增加的抗炎性 CD16 单核细胞，是血液中 表达的主要来源。用抗炎性白细胞介素 10 处理可转录激活 。激活抗炎和抑制促炎基因表达。增加 水平导致更多 CD16 单核细胞的出现。与 S100A9 结合，导致单核细胞亚型转换，从而减少炎症。结果，在炎症期间改善内皮屏障完整性，并促进小鼠损伤后的血管愈合。
这些结果描述了一种新的内源性抗炎途径，涉及将单核细胞亚型转化为抗炎性 CD16 单核细胞。该数据为长非编码 RNA 类提供了一种新的功能，可防止蛋白质分泌，并表明长非编码 RNA 可作为心脏免疫学领域干预措施的潜在靶点。
