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CD98 regulates vascular smooth muscle cell proliferation in atherosclerosis

  • Author Footnotes
    1 These authors contributed equally to this work.
    Yvonne Baumer
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Sara McCurdy
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
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  • Martin Alcala
    Affiliations
    Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain
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  • Nehal Mehta
    Affiliations
    Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States
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  • Bog-Hieu Lee
    Correspondence
    Corresponding author.
    Affiliations
    Department of Food and Nutrition, School of Food Science and Technology, Chung-Ang University, Seoul, South Korea
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  • Mark H. Ginsberg
    Affiliations
    Department of Medicine, University of California San Diego, La Jolla, CA, United States
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  • William A. Boisvert
    Correspondence
    Corresponding author. Center for Cardiovascular Research, University of Hawaii, John A. Burns School of Medicine, 651 Ilalo Street, Honolulu, HI 96813, United States.
    Affiliations
    Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States

    Kazan Federal University, Kazan, Russia
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  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • CD98 deficiency severely limits vascular smooth muscle cell proliferation.
      • Atherosclerotic mice lacking CD98 in their smooth muscle cells have reduced vascular smooth muscle cells in their plaque.
      • Plaques from CD98-deficient mice have significantly larger necrotic core.
      • Breaks in elastin layer of atherosclerotic plaques are reduced in CD98 deficiency.
      • CD98 may play an important role in plaque stability.

      Abstract

      Background and aims

      Vascular smooth muscle cells (VSMC) migrate and proliferate to form a stabilizing fibrous cap that encapsulates atherosclerotic plaques. CD98 is a transmembrane protein made of two subunits, CD98 heavy chain (CD98hc) and one of six light chains, and is known to be involved in cell proliferation and survival. Because the influence of CD98hc on atherosclerosis development is unknown, our aim was to determine if CD98hc expressed on VSMC plays a role in shaping the morphology of atherosclerotic plaques by regulating VSMC function.

      Methods

      In addition to determining the role of CD98hc in VSMC proliferation and apoptosis, we utilized mice with SMC-specific deletion of CD98hc (CD98hcfl/flSM22αCre+) to determine the effects of CD98hc deficiency on VSMC function in atherosclerotic plaque.

      Results

      After culturing for 5 days in vitro, CD98hc−/− VSMC displayed dramatically reduced cell counts, reduced proliferation, as well as reduced migration compared to control VSMC. Analysis of aortic VSCM after 8 weeks of HFD showed a reduction in CD98hc−/− VSMC proliferation as well as increased apoptosis compared to controls. A long-term atherosclerosis study using SMC-CD98hc−/−/ldlr−/− mice was performed. Although total plaque area was unchanged, CD98hc−/− mice showed reduced presence of VSMC within the plaque (2.1 ± 0.4% vs. 4.3 ± 0.4% SM22α-positive area per plaque area, p < 0.05), decreased collagen content, as well as increased necrotic core area (25.8 ± 1.9% vs. 10.9 ± 1.6%, p < 0.05) compared to control ldlr−/− mice.

      Conclusions

      We conclude that CD98hc is required for VSMC proliferation, and that its deficiency leads to significantly reduced presence of VSMC in the neointima. Thus, CD98hc expression in VSMC contributes to the formation of plaques that are morphologically more stable, and thereby protects against atherothrombosis.

      Keywords

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