CD98 regulates vascular smooth muscle cell proliferation in atherosclerosis

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.

Puerarin inhibits vascular smooth muscle cells proliferation induced by fine particulate matter via suppressing of the p38 MAPK signaling pathway

“…During progression of atherosclerosis, transformation of VSMCs from the quiescent contractile phenotype towards the proliferative migratory phenotype into the plaque area to form a fibrous cap is generally regarded as a vital step in the formation of unstable atherosclerotic plaques [ 24 ]. These VSMCs that migrated into the intima exhibit an aberrantly increased proliferation and extracellular matrix production, leading to the formation of the fibrous cap in atherosclerotic lesions [ 25 ]. Endothelial NO produced by NO synthase (eNOS) induces vascular smooth muscle relaxation and suppresses the aggregation and adhesion of inflammatory cells and platelets [ 26 ].…”

Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis

“…Secondly, Ldlr −/− mice were put on HFD for 0–3 weeks, the aorta isolated and thoroughly cleaned, digested using Liberase TM (Roche), as described previously 50 and E-selectin expression was quantified using flow cytometry. Data were analyzed using FlowJo software according to the flow chart in Supplementary Fig.…”

Extracellular Matrix Metalloproteinase Inducer EMMPRIN (CD147) in Cardiovascular Disease

“…CD98 is a type II transmembrane protein and consists of a heavy chain (CD98hc) and a light chain and associates with EMMPRIN via the EC1 domain [ 22 , 42 ]. Moreover, EMMPRIN seems to be involved in regulating the surface expression of CD98.…”

“…These interactions (EMMPRIN with CD98hc, CD98hc with LAT1, and EMMPRIN with MCTs) result in the formation of a large MCT-EMMPRIN-CD98hc-LAT1 complex, which plays a critical role in cellular energy metabolism [ 22 ]. Of note, CD98hc is upregulated during plaque formation in low density lipoprotein receptor deficient (Ldlr −/− ) mice in vivo, and the presence of CD98hc in the plaque leads to an elevated migration of vascular smooth muscle cells and thus a stabilization of the atherosclerotic plaque [ 42 , 44 ].…”