Ceramide and Ischemia/Reperfusion Injury

Abstract

Ceramide, a bioactive membrane sphingolipid, functions as an important second messenger in apoptosis and cell signaling. In response to stresses, it may be generated by de novo synthesis, sphingomyelin hydrolysis, and/or recycling of complex sphingolipids. It is cleared from cells through the activity of ceramidases, phosphorylation to ceramide-1-phosphate, or resynthesis into more complex sphingolipids. Ischemia/reperfusion (IR) injury occurs when oxygen/nutrition is rapidly reintroduced into ischemic tissue, resulting in cell death and tissue damage, and is a major concern in diverse clinical settings, including organ resection and transplantation. Numerous reports show that ceramide levels are markedly elevated during IR. Mitochondria are major sites of reactive oxygen species (ROS) production and play a key role in IR-induced and ceramide-mediated cell death and tissue damage. During the development of IR injury, the initial response of ROS and TNF-alpha production activates two major ceramide generating pathways (sphingomyelin hydrolysis and de novo ceramide synthesis). The increased ceramide has broad effects depending on the IR phases, including both pro- and antiapoptotic effects. Therefore, strategies that reduce the levels of ceramide, for example, by modulation of ceramidase and/or sphingomyelinases activities, may represent novel and promising therapeutic approaches to prevent or treat IR injury in diverse clinical settings.

Ceramide and Regulation of Vascular Tone

“…The ability of ROS to activate different ceramide generating pathways has been extensively studied in many cell types [52,53,54,55]. Thus, a number of reports have indicated that the generation of ROS in response to various stimuli such as antileukemic agents [56], stress [57], ischemia-reperfusion [58], pathogens [59], or hypoxia [26,27] may lead to ceramide accumulation. Both nSMase and aSMase are redox-sensitive enzymes whose activities are incremented by ROS [51,53,55].…”

The Cross-Talk Between Sphingolipids and Insulin-Like Growth Factor Signaling: Significance for Aging and Neurodegeneration

“…The role of mitochondria in cell death signaling by ceramide has been reviewed extensively [ 247 , 248 ]. However, evidence is accumulating on ceramide roles in a whole spectrum of regulatory events that affect their function.…”

DHA and 19,20-EDP induce lysosomal-proteolytic-dependent cytotoxicity through de novo ceramide production in H9c2 cells with a glycolytic profile

“…Ceramide is a central lipid component of sphingolipid structure that is biosynthesized by three pathways, which include de novo synthesis from palmitoyl-CoA and serine, hydrolysis of sphingomyelin or a salvage pathway 17 . It is an important lipid mediator regulating various cellular responses like cell death, and recent evidence also suggests a role in various metabolic pathways influencing mitochondrial function 18 . In vitro data indicate production of ceramide increases in glycolytic cells but decreases in cells with developed OXPHOS 19 .…”