Pharmacological Activation of Peroxisome Proliferator-Activated Receptor {Delta} Increases Sphingomyelin Synthase Activity in THP-1 Macrophage-Derived Foam Cell

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which mediate glucose and lipid homeostasis by regulating the expression of a large number of transcription factors. Sphingomyelin synthase (SMS) is a key enzyme in the synthesis of sphingomyelin (SM), and its expression and activity have been reported to be associated with atherosclerosis (AS). Although there have been many functional PPAR and SMS studies on atherosclerosis in recent years, few have investigated the correlation between the activation of PPARδ and the activity of SMS. In his study, macrophage-induced foam cells were utilized to model important pathological changes that occur in AS. The influence of PPARδ agonism by GW501516 on SMS and its product molecule SM were measured. Results indicated that the activation of PPARδ was correlated in a positive manner with the activity of SMS2, and the content of SM was dose dependently increased by GW501516. Together, this study represents the first to suggest that PPARδ activation may be a potential risk of AS through enhancing activity of SMS2.

Sphingomyelin synthase 2 promotes H2O2-induced endothelial dysfunction by activating the Wnt/β-catenin signaling pathway

“…All of these results suggested that SMS2 is involved in AS occurrence and development via promoting HUVECs dysfunction and adhesion ability to THP-1 cells. Although previous studies have verified that SMS contributes to AS occurrence and development through the inhibition of RCT and may lead to lipid deposition ( 13 – 15 , 40 , 33 ), to the best of our knowledge, the present study is the first to suggest that SMS2 may promote HUVEC dysfunction and adhesion ability to THP-1 cells, and assist in AS occurrence and development.…”

“…For example, epidemiological studies and clinical trial data identified that serum SM content and AS were positively correlated ( 11 , 12 ). Animal and cellular experiments have also indicated that SMS may cause AS by inhibiting reverse cholesterol transport (RCT), leading to lipid deposition ( 13 - 15 ). However, these studies were focused on the effects of SM on the RCT monocyte-macrophage infiltration and lipid deposition ( 13 – 15 ).…”

“…Animal and cellular experiments have also indicated that SMS may cause AS by inhibiting reverse cholesterol transport (RCT), leading to lipid deposition ( 13 - 15 ). However, these studies were focused on the effects of SM on the RCT monocyte-macrophage infiltration and lipid deposition ( 13 – 15 ). Although Zhou et al ( 16 ) hypothesized that lovastatin may decrease the levels of sphingomyelin increased by 27-hydroxycholesterol on cultured vascular ECs and may attenuate cellular calcification, the role of SM in endothelial dysfunction remains unclear.…”

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

“…Although this study did not assess the reason for this specificity, it is likely to be related to increased Aβ production of the cells. Aβ1‐42 has been shown to activate nSMase, which participates in the production of ceramides (Mou, Yang, Qu, Chen, & Zhang, ). In contrast, ceramides have been shown to further increase the production of Aβ1‐42 (Grimm et al, ).…”

【Original Contribution】 Plasma and Erythrocyte Membrane Plasmalogen Diminished in Severe Atherosclerotic Patients Undergoing Endovascular Therapy

“…SM is synthetized by SM synthase. This enzyme is activated by peroxisome proliferator-activated receptor (PPAR-) signaling pathway inducing inflammation, and this enzymatic activity is reported to link to atherosclerosis 25) . Moreover, sphingolipids including SM are reported to be accumulated in human coronary plaque and are acting as inducers of atheromatous plaque inflammation and instability 26) .…”