Adiponectin mediated metabolic and sphingolipid alterations in preventing endothelial dysfunction.

Abstract

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.