Baumer Yvonne, McCurdy Sara, Alcala Martin, Mehta Nehal, Lee Bog-Hieu, Ginsberg Mark H, Boisvert William A
Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States.
Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
Atherosclerosis. 2017 Jan;256:105-114. doi: 10.1016/j.atherosclerosis.2016.11.017. Epub 2016 Nov 16.
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.
In addition to determining the role of CD98hc in VSMC proliferation and apoptosis, we utilized mice with SMC-specific deletion of CD98hc (CD98hcSM22αCre) to determine the effects of CD98hc deficiency on VSMC function in atherosclerotic plaque.
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.
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.
血管平滑肌细胞（VSMC）迁移并增殖，形成包裹动脉粥样硬化斑块的稳定纤维帽。CD98是一种由两个亚基组成的跨膜蛋白，即CD98重链（CD98hc）和六种轻链之一，已知其参与细胞增殖和存活。由于CD98hc对动脉粥样硬化发展的影响尚不清楚，我们的目的是确定VSMC上表达的CD98hc是否通过调节VSMC功能在塑造动脉粥样硬化斑块形态方面发挥作用。
除了确定CD98hc在VSMC增殖和凋亡中的作用外，我们还利用平滑肌细胞特异性缺失CD98hc的小鼠（CD98hcSM22αCre）来确定CD98hc缺乏对动脉粥样硬化斑块中VSMC功能的影响。
体外培养5天后，与对照VSMC相比，CD98hc VSMC的细胞计数显著减少，增殖和迁移能力降低。高脂饮食8周后对主动脉VSCM的分析显示，与对照相比，CD98hc VSMC增殖减少，凋亡增加。使用SMC-CD98hc/ldlr小鼠进行了一项长期动脉粥样硬化研究。尽管总斑块面积没有变化，但与对照ldlr小鼠相比，CD98hc小鼠斑块内VSMC的存在减少（每个斑块面积中SM22α阳性面积为2.1±0.4%对4.3±0.4%，p<0.05），胶原含量降低，坏死核心面积增加（25.8±1.9%对10.9±1.6%，p<0.05）。
我们得出结论，VSMC增殖需要CD98hc，其缺乏导致新生内膜中VSMC的存在显著减少。因此，VSMC中CD98hc的表达有助于形成形态上更稳定的斑块，从而预防动脉粥样硬化血栓形成。
