Human Blood-Derived Macrophages Induce Apoptosis in Human Plaque-Derived Vascular Smooth Muscle Cells by Fas-Ligand/Fas Interactions

Redox factor-1 (Ref-1) is a multifunctional protein that regulates redox, DNA repair, and the response to cell stress. We previously demonstrated that Ref-1+/− mice exhibit a significantly reduced Ref-1 mRNA and protein levels within the vasculature, which are associated with increased oxidative stress. The goal of this study was to test the hypothesis that partial loss of Ref-1 altered the cellular response to vascular injury. Fourteen days after femoral artery wire injury, we found that vessel intima-to-media ratio was significantly reduced in Ref-1+/− mice compared with that in wild-type mice ( P < 0.01). Bromodeoxyuridine labeling and transferase-mediated dUTP nick-end labeling staining at 14 days did not differ in the Ref-1+/− mice. In vitro studies found no significant changes in either serum-induced proliferation or baseline apoptosis in Ref-1+/− vascular smooth muscle cells. Exposure to Fas ligand; however, did result in increased susceptibility of Ref-1+/− vascular smooth muscle cells to apoptosis ( P < 0.001). Ref-1+/− mice exhibited an increase in circulating baseline levels of IL-10, IL-1α, and VEGF compared with those in wild-type mice but a marked impairment in these pathways in response to injury. In sum, loss of a single allele of Ref-1 is sufficient to reduce intimal lesion formation and to alter circulating cytokine and growth factor expression.

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Fas/Fas ligand-mediated death pathway is involved in oxLDL-induced apoptosis in vascular smooth muscle cells

AJP Cell Physiology ◽

10.1152/ajpcell.2001.280.3.c709 ◽

2001 ◽

Vol 280 (3) ◽

pp. C709-C718 ◽

Cited By ~ 64

Author(s):

Tzong-Shyuan Lee ◽

Lee-Young Chau

Keyword(s):

Cell Death ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Fas Ligand ◽

Density Lipoprotein ◽

Muscle Cells ◽

Potent Inducer ◽

Apoptotic Death

Oxidized low-density lipoprotein (oxLDL) is a potent inducer of apoptosis for vascular cells. In the present study, we demonstrate that the expression of death mediators, including p53, Fas, and Fas ligand (FasL) was substantially upregulated by oxLDL in cultured vascular smooth muscle cells (SMCs). The induction of these death mediators was time dependent and was accompanied by an increase in apoptotic death of SMCs following oxLDL treatment. Two oxysterols, 7β-hydroxycholesterol and 25-hydroxycholesterol, were also effective to induce the expression of death mediators and apoptosis. α-Tocopherol and deferoxamine significantly attenuated the induction of death mediators and cell death induced by oxLDL and oxysterols, suggesting that reactive oxygen species are involved in triggering the apoptotic event. Incubation of cells with FasL-neutralizing antibody inhibited the oxLDL-induced cell death up to 50%. Furthermore, caspase 8 and caspase 3 activities were induced time dependently in SMCs following oxLDL treatment. Collectively, these data suggest that the Fas/FasL death pathway is activated and responsible for, at least in part, the apoptotic death in vascular SMCs upon exposure to oxLDL.

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