Plasma membrane reorganization links acid sphingomyelinase/ceramide to p38 MAPK pathways in endothelial cells apoptosis.
The p38 MAPK signaling pathway is essential in the cellular response to stress stimuli, in particular in the endothelial cells that are major target of external stress. The importance of the bioactive sphingolipid ceramide generated by acid sphingomyelinase is also firmly established in stress-induced endothelial apoptotic cell death. Despite a suggested link between the p38 MAPK and ceramide pathways, the exact molecular events of this connection remain elusive. In the present study, by using two different activators of p38 MAPK, namely anisomycin and ionizing radiation, we depicted how ceramide generated by acid sphingomyelinase was involved in p38 MAPK-dependent apoptosis of endothelial cells. We first proved that both anisomycin and ionizing radiation conducted to apoptosis through activation of p38 MAPK in human microvascular endothelial cells HMEC-1. We then found that both treatments induced activation of acid sphingomyelinase and the generation of ceramide. This step was required for p38 MAPK activation and apoptosis. We finally showed that irradiation, as well as treatment with exogenous C16-ceramide or bacterial sphingomyelinase, induced in endothelial cells a deep reorganization of the plasma membrane with formation of large lipid platforms at the cell surface, leading to p38 MAPK activation and apoptosis in endothelial cells. Altogether, our results proved that the plasma membrane reorganization leading to ceramide production is essential for stress-induced activation of p38 MAPK and apoptosis in endothelial cells and established the link between the acid sphingomyelinase/ceramide and p38 MAPK pathways.
CRCNA, INSERM, CNRS, Université de Nantes, Nantes, France.
Colin
C
Niaudet
CRCNA, INSERM, CNRS, Université de Nantes, Nantes, France.
Stéphanie
S
Bonnaud
CRCNA, INSERM, CNRS, Université de Nantes, Nantes, France.
Maëva
M
Guillonneau
CRCNA, INSERM, CNRS, Université de Nantes, Nantes, France.
Sébastien
S
Gouard
CRCNA, INSERM, CNRS, Université de Nantes, Nantes, France; IRSN, Fontenay-aux-roses, France.
Marie-Hélène
MH
Gaugler
CRCNA, INSERM, CNRS, Université de Nantes, Nantes, France.
Soizic
S
Dutoit
CRCNA, INSERM, CNRS, Université de Nantes, Nantes, France.
Natacha
N
Ripoche
CRCNA, INSERM, CNRS, Université de Nantes, Nantes, France.
Nolwenn
N
Dubois
LPRO, INSERM, Université de Nantes, Nantes, France.
Valérie
V
Trichet
CRCNA, INSERM, CNRS, Université de Nantes, Nantes, France.
Isabelle
I
Corre
CRCNA, INSERM, CNRS, Université de Nantes, Nantes, France; Laboratoire de Biologie du Cancer et Théranostique, ICO, Saint-Herblain, France. Electronic address: francois.paris@inserm.fr.
François
F
Paris
D017209:Apoptosis; D002462:Cell Membrane / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D020935:MAP Kinase Signaling System; D021962:Membrane Microdomains / Q000378:metabolism; D008954:Models, Biological; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013312:Stress, Physiological; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D002518:Ceramides; D048051:p38 Mitogen-Activated Protein Kinases; D013108:Sphingomyelin Phosphodiesterase
Apoptosis; Ceramide; Endothelium; Membrane remodeling; Stress signaling; p38 MAPK