Attenuation by Statins of Membrane Raft-Redox Signaling in Coronary Arterial Endothelium

Abstract

Membrane raft (MR)-redox signaling platforms associated with NADPH oxidase are involved in coronary endothelial dysfunction. Here, we studied whether statins interfere with the formation of MR-redox signaling platforms to protect the coronary arterial endothelium from oxidized low-density lipoprotein (OxLDL)-induced injury and from acute hypercholesterolemia. In cultured human coronary arterial endothelial cells, confocal microscopy detected the formation of an MRs clustering when they were exposed to OxLDL, and such MR platform formation was inhibited markedly by statins, including pravastatin and simvastatin. In these MR clusters, NADPH oxidase subunits gp91 phox and p47 phox were aggregated and were markedly blocked by both statins. In addition, colocalization of acid sphingomyelinase (ASM) and ceramide was induced by OxLDL, which was blocked by statins. Electron spin resonance spectrometry showed that OxLDL-induced superoxide (O 2 .2 ) production in the MR fractions was substantially reduced by statins. In coronary artery intima of mice with acute hypercholesterolemia, confocal microscopy revealed a colocalization of gp91 phox , p47 phox , ASM, or ceramide in MR clusters. Such colocalization was rarely observed in the arteries of normal mice or significantly reduced by pretreatment of hypercholesterolemic mice with statins. Furthermore, O 2 .2 production in situ was 3-fold higher in the coronary arteries from hypercholesterolemic mice than in those from normal mice, and such increase was inhibited by statins. Our results indicate that blockade of MR-redox signaling platform formation in endothelial cell membrane may be another important therapeutic mechanism of statins in preventing endothelial injury and atherosclerosis and may be associated with their direct action on membrane cholesterol structure and function.

Regulation of the Inflammasome by Ceramide in Cystic Fibrosis Lungs

“…Since clustering of CD95 in ceramide-enriched membrane domains is pre-requisite for signaling via this receptor [37,38], ceramide may also activate the inflammasome by clustering and stimulation of CD95. In addition, ceramide may trigger a slow, but constant release of reactive oxygen species in epithelial cells from cystic fibrosis mice by clustering NADPH-oxidase in ceramide-enriched membrane domains as previously shown for instance in podocytes, endothelial cells, monocytes and macrophages [39,40,41,42,43]. …”

Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction

“…Indeed, statins have been reported to decrease membrane cholesterol levels in various cell types. 35,36 Moreover, mevalonate, the cholesterol intermediate just downstream of HMG-CoA, reverses statin-induced inhibition of MTOR signaling, 37,38 indicating that HMGCR inhibition is required for the suppression of MTOR activity. However, additional studies are needed to confirm that statins reduce membrane cholesterol level in hepatocytes and that statin-induced autophagy and gluconeogenesis are mediated through the suppression of MTOR activity.…”

Plasma sphingolipids and depressive symptoms in coronary artery disease

“…All participants were required to be taking a statin medication. This inclusion criterion was implemented in order to standardize the study population, as statins are the standard of care in CAD and may impact sphingolipid concentrations (Ng et al., 2014; Wei et al., 2013) as well as mood and cognition (Kim et al., 2015; Power, Weuve, Sharrett, Blacker, & Gottesman, 2015). …”