Vincent Vinnyfred, Thakkar Himani, Sen Atanu, Bansal Ashutosh, Das Ujjalkumar Subhash, Gunasekaran Abishek, Bhatla Neerja, Velpandian Thirumurthy, Singh Archna
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
Mol Cell Biochem. 2025 Mar 26. doi: 10.1007/s11010-025-05268-1.
Endothelial dysfunction is an early indicator of atherosclerosis. Adiponectin, a hormone secreted by adipose tissue with insulin-sensitizing and anti-inflammatory properties, offers protection against atherosclerosis. This study investigated the metabolic and sphingolipid alterations in endothelial cells linked to the protective effects of adiponectin against endothelial dysfunction. Human Umbilical Endothelial Cells (HUVECs) were treated with Tumor Necrosis Factor-alpha (TNF-α) to induce endothelial dysfunction. AdipoRon and SKI-I were used to study the effects of adiponectin and sphingosine kinase inhibition in HUVECs. Metabolic changes and sphingolipid alterations were assessed to understand changes in lipid metabolism, and RNA sequencing was used to quantify the transcriptomics changes. TNF-α treatment significantly upregulated glycolysis and downregulated long-chain fatty acid oxidation and mitochondrial ATP production, while AdipoRon co-treatment partially reversed these metabolic effects. In HUVECs, TNF-α treatment increased intracellular C16 and C18 ceramides and Sphingosine 1-Phosphate (S1P) while decreasing extracellular S1P. AdipoRon Co-treatment reversed these effects; AdipoRon also reversed the transcriptional changes induced by TNF-α. Sphingosine kinase inhibition in HUVECs led to mitochondrial dysfunction at the metabolic and transcriptional levels. This study provides insights into potential therapeutic strategies targeting endothelial metabolism while unraveling a novel mitochondrial modulation mediated by sphingosine kinases in endothelial cells.
内皮功能障碍是动脉粥样硬化的早期指标。脂联素是一种由脂肪组织分泌的具有胰岛素增敏和抗炎特性的激素，可预防动脉粥样硬化。本研究调查了与脂联素对内皮功能障碍的保护作用相关的内皮细胞代谢和鞘脂改变。用人脐静脉内皮细胞（HUVECs）经肿瘤坏死因子-α（TNF-α）处理以诱导内皮功能障碍。使用AdipoRon和SKI-I研究脂联素和鞘氨醇激酶抑制对HUVECs的影响。评估代谢变化和鞘脂改变以了解脂质代谢的变化，并使用RNA测序来量化转录组学变化。TNF-α处理显著上调糖酵解并下调长链脂肪酸氧化和线粒体ATP生成，而AdipoRon联合处理部分逆转了这些代谢效应。在HUVECs中，TNF-α处理增加细胞内C16和C18神经酰胺以及1-磷酸鞘氨醇（S1P），同时降低细胞外S1P。AdipoRon联合处理逆转了这些效应；AdipoRon还逆转了TNF-α诱导的转录变化。HUVECs中的鞘氨醇激酶抑制在代谢和转录水平上导致线粒体功能障碍。本研究为针对内皮代谢的潜在治疗策略提供了见解，同时揭示了内皮细胞中由鞘氨醇激酶介导的新型线粒体调节。
