Intercellular Adhesion Molecule 1 Engagement Modulates Sphingomyelinase and Ceramide, Supporting Uptake of Drug Carriers by the Vascular Endothelium

Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 32 Số 5 - Trang 1178-1185 - 2012
Daniel Serrano1, Tridib Kumar Bhowmick2, Rishi Chadha3, Carmen Garnacho4, Silvia Muro5
1Daniel Serrano From the Department of Cell Biology and Molecular Genetics (D.S.), Biological Sciences Graduate Program (D.S.), Institute for Biosciences and Biotechnology Research (T.B., R.C., C.G., S.M.), and Fischell Department of Bioengineering (S.M.), University of Maryland, College Park, MD.
2Tridib Bhowmick From the Department of Cell Biology and Molecular Genetics (D.S.), Biological Sciences Graduate Program (D.S.), Institute for Biosciences and Biotechnology Research (T.B., R.C., C.G., S.M.), and Fischell Department of Bioengineering (S.M.), University of Maryland, College Park, MD.
3Rishi Chadha From the Department of Cell Biology and Molecular Genetics (D.S.), Biological Sciences Graduate Program (D.S.), Institute for Biosciences and Biotechnology Research (T.B., R.C., C.G., S.M.), and Fischell Department of Bioengineering (S.M.), University of Maryland, College Park, MD.
4Carmen Garnacho From the Department of Cell Biology and Molecular Genetics (D.S.), Biological Sciences Graduate Program (D.S.), Institute for Biosciences and Biotechnology Research (T.B., R.C., C.G., S.M.), and Fischell Department of Bioengineering (S.M.), University of Maryland, College Park, MD.
5Silvia Muro From the Department of Cell Biology and Molecular Genetics (D.S.), Biological Sciences Graduate Program (D.S.), Institute for Biosciences and Biotechnology Research (T.B., R.C., C.G., S.M.), and Fischell Department of Bioengineering (S.M.), University of Maryland, College Park, MD.

Tóm tắt

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. Conclusion— 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.

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Thông tin xuất bản

Arteriosclerosis, Thrombosis, and Vascular Biology

Tập 32 Số 5

1178-1185

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