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Dependence of proliferative vascular smooth muscle cells on CD98hc (4F2hc, SLC3A2).

Journal article
Authors Per Fogelstrand
Chloé C Féral
Ramin Zargham
Mark H Ginsberg
Published in The Journal of experimental medicine
Volume 206
Issue 11
Pages 2397-406
ISSN 1540-9538
Publication year 2009
Published at Institute of Medicine
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 2397-406
Language en
Links dx.doi.org/10.1084/jem.20082845
Keywords Amino Acid Transport Systems, metabolism, Animals, Antigens, CD98 Heavy Chain, metabolism, Carotid Arteries, metabolism, pathology, Cell Proliferation, Cell Survival, Cells, Cultured, Gene Deletion, Hyperplasia, Integrases, metabolism, Integrins, metabolism, Mice, Microfilament Proteins, metabolism, Muscle Proteins, metabolism, Muscle, Smooth, Vascular, cytology, Myocytes, Smooth Muscle, cytology, metabolism, Protein Binding, Tunica Intima, metabolism, pathology
Subject categories Cell Biology, Vascular surgery

Abstract

Activation of vascular smooth muscle cells (VSMCs) to migrate and proliferate is essential for the formation of intimal hyperplasia. Hence, selectively targeting activated VSMCs is a potential strategy against vaso-occlusive disorders such as in-stent restenosis, vein-graft stenosis, and transplant vasculopathy. We show that CD98 heavy chain (CD98hc) is markedly up-regulated in neointimal and cultured VSMCs, and that activated but not quiescent VSMCs require CD98hc for survival. CD98hc mediates integrin signaling and localizes amino acid transporters to the plasma membrane. SMC-specific deletion of CD98hc did not affect normal vessel morphology, indicating that CD98hc was not required for the maintenance of resident quiescent VSMCs; however, CD98hc deletion reduced intimal hyperplasia after arterial injury. Ex vivo and in vitro, loss of CD98hc suppressed proliferation and induced apoptosis in VSMCs. Furthermore, reconstitution with CD98hc mutants showed that CD98hc interaction with integrins was necessary for the survival of VSMCs. These studies establish the importance of CD98hc in VSMC proliferation and survival. Furthermore, loss of CD98hc was selectively deleterious to activated VSMCs while sparing resident quiescent VSMCs, suggesting that activated VSMCs are physiologically dependent on CD98hc, and hence, CD98hc is a potential therapeutic target in vaso-occlusive disorders.

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