Intercellular adhesion molecule 1 engagement modulates sphingomyelinase and ceramide, supporting uptake of drug carriers by the vascular endothelium.

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TitleIntercellular adhesion molecule 1 engagement modulates sphingomyelinase and ceramide, supporting uptake of drug carriers by the vascular endothelium.
Publication TypeJournal Article
Year of Publication2012
AuthorsSerrano, D, Bhowmick, T, Chadha, R, Garnacho, C, Muro, S
JournalArterioscler Thromb Vasc Biol
Date Published2012 May
KeywordsAnimals, Cells, Cultured, Ceramides, Drug Carriers, Endocytosis, Endothelium, Vascular, Humans, Intercellular Adhesion Molecule-1, Mice, Mice, Inbred C57BL, Microscopy, Electron, Signal Transduction, Sphingomyelin Phosphodiesterase

OBJECTIVE: Engagement of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells by ICAM-1-targeted carriers induces cell adhesion molecule-mediated endocytosis, providing intraendothelial delivery of therapeutics. This pathway differs from classical endocytic mechanisms and invokes aspects of endothelial signaling during inflammation. ICAM-1 interacts with Na(+)/H(+) exchanger NHE1 during endocytosis, but it is unclear how this regulates plasmalemma and cytoskeletal changes. We studied such aspects in this work.

METHODS AND RESULTS: We used fluorescence and electron microscopy, inhibitors and knockout tools, cell culture, and mouse models. ICAM-1 engagement by anti-ICAM carriers induced sphingomyelin-enriched engulfment structures. Acid sphingomyelinase (ASM), an acidic enzyme that hydrolyzes sphingomyelin into ceramide (involved in plasmalemma deformability and cytoskeletal reorganization), redistributed to ICAM-1-engagement sites at ceramide-enriched areas. This induced actin stress fibers and carrier endocytosis. Inhibiting ASM impaired ceramide enrichment, engulfment structures, cytoskeletal reorganization, and carrier uptake, which was rescued by supplying this enzyme activity exogenously. Interfering with NHE1 rendered similar outcomes, suggesting that Na(+)/H(+) exchange might provide an acidic microenvironment for ASM at the plasmalemma.

CONCLUSIONS: These findings are consistent with the ability of endothelial cells to internalize relatively large ICAM- 1--targeted drug carriers and expand our knowledge on the regulation of the sphingomyelin/ceramide pathway by the vascular endothelium.

Alternate JournalArterioscler. Thromb. Vasc. Biol.
PubMed ID22328778
PubMed Central IDPMC3331944
Grant ListR01 HL098416-03 / HL / NHLBI NIH HHS / United States
R01 HL098416-04 / HL / NHLBI NIH HHS / United States
R01-HL098416 / HL / NHLBI NIH HHS / United States