High-density lipoprotein induces cyclooxygenase-2 expression and prostaglandin I-2 release in endothelial cells through sphingosine kinase-2

Abstract

High-density lipoprotein (HDL) has a significant cardioprotective effects. HDL induces cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release in vascular endothelial cells, which contributes to its anti-atherogenic effects. However, the underlying mechanisms are not fully understood. In the present study, we observed that HDL-stimulated COX-2 expression and PGI-2 production in human umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent manner. These effects triggered by HDL were inhibited by pertussis toxin (PTX), protein kinase C (PKC) inhibitor GF109203X, and ERK inhibitor PD98059, suggesting that Gαi/Gαo-coupled GPCR, PKC, and ERK pathways are involved in HDL-induced COX-2/PGI-2 activation. More importantly, we found that silencing of sphingosine kinase 2 (SphK-2) also blocked HDL-induced COX-2/PGI-2 activation. In addition, HDL-activated SphK-2 phosphorylation accompanied by increased S1P level in the nucleus. Our ChIP data demonstrated that SphK-2 is associated with CREB at the COX-2 promoter region. Collectively, these results indicate that HDL induces COX-2 expression and PGI-2 release in endothelial cells through activation of PKC, ERK1/2, and SphK-2 pathways. These findings implicate a novel mechanism underlying anti-atherothrombotic effects of HDL.

Alterations in the Expression of the NF-κB Family Member RelB as a Novel Marker of Cardiovascular Outcomes during Acute Exacerbations of Chronic Obstructive Pulmonary Disease

“…As with RelB expression, several of these mediators exhibited strong associations with cardiovascular alterations. Cox-2 is induced by HDL [46] and LDL [47] , and although an association between Cox-2 and blood pressure has been described [48] , [49] , our study is first to suggest a relationship with cfPWV and AIx, two measures of arterial stiffening associated with cardiovascular risk. Moreover, the positive relationship between Cox-2 and RBC diameter width is novel and may be of clinical significance, as RBC diameter width-distribution is a powerful outcome predictor in chronic and/or acute left heart failure, and in COPD, can help identify right ventricle failure [50] .…”

Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages

“…Hence, even though the effect of FFA4-S on PMA-induced ROS generation was significantly more profound than that of FFA4-L, catalase upregulation likely only plays a partial role in absolving acute ROS generation. While canonical signaling of GPCRs has been shown to modulate COX-2 expression patterns (38–43), a recent study found that the C-terminal tail of the angiotensin-II type 1 GPCR regulated COX-2 expression in a manner independent of canonical signals, including phosphorylation of the C-terminal tail and β-arrestin recruitment (44). Rather, ATII-1R decreases COX-2 expression via direct enhancement of COX-2 ubiquitination and subsequent proteosomal degradation, an effect that was facilitated by the C-terminal tail in absence of the rest of the GPCR (44).…”

HDL and Atherothrombotic Vascular Disease

“…Similar to NO, there is evidence to suggest that the release of the endothelium-derived vasodilator prostacyclin can be influenced by HDLs. In human umbilical vein endothelial cells, HDLs elevated cyclooxygenase-2 protein expression and thereby induced prostacyclin synthesis via a pathway that involved PKC, ERK1/2, and sphingosine kinase SphK-2 (Xiong et al 2014). The human relevance of these findings is underscored by studies demonstrating that infusion of rHDLs in hypercholesterolemic patients led to normalization of endothelium-dependent vasodilation in response to acetylcholine (Spieker et al 2002).…”