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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kirurgi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Surgery (hsv//eng)

NATURVETENSKAP  -- Biologi -- Cellbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Cell Biology (hsv//eng)

Nyckelord

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

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)