Hypertensive stretch regulates endothelial cell inflammation and apoptosis through ceramide metabolism.

Hypertension and cardiovascular disease are associated with elevated plasma levels of ceramides (Cer), a type of membrane sphingolipids (SPLs). Increased cellular Cer levels are known to cause vascular endothelial cell (EC) dysfunction. However, Cer metabolism changes due to EC exposure to high-magnitude "hypertensive" cyclic stretch (HCS) and their role in EC dysfunction are poorly defined. Cultured human ECs exposed to HCS (15% elongation at 1 Hz, 24 h) exhibited increased oxidative stress, upregulation of genes for cytokines and leukocyte adhesion molecules, increased inflammatory response to a low concentration of tumor necrosis factor-α, and increased apoptosis compared with ECs exposed to "normotensive" CS (NCS; 5% elongation at 1 Hz, 24 h). Lipidomics analysis of EC pellets at 4 or 24 h of CS detected no difference in Cer levels and significantly higher sphingomyelin (SM) levels at 24 h of HCS compared with NCS. Cer immunostaining showed significantly higher Cer levels at both the perinuclear and peripheral subcellular regions in HCS compared with the corresponding regions in NCS. HCS significantly increased the concentrations of certain long-chain Cer in the extracellular media compared with NCS. Pharmacological inhibition of key enzymes in Cer biosynthesis, that is, de novo synthesis and SM hydrolysis pathways, significantly inhibited HCS-induced EC inflammation and apoptosis, suggesting that Cer generated from SM, via the sphingomyelinase family of enzymes, and accumulated at specific subcellular compartments may be responsible for the HCS-induced EC dysfunction. In summary, Cer act as mechanotransducers that connect hypertensive stretch to EC inflammation and apoptosis and promote CVD.