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(American Journal of Pathology. 2006;168:2054-2063.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.050473

Interferon- Induces Fas Trafficking and Sensitization to Apoptosis in Vascular Smooth Muscle Cells via a PI3K- and Akt-Dependent Mechanism

Dalya Rosner^*, Victoria Stoneman^*, Trevor Littlewood^*, Nicola McCarthy^*, Nichola Figg^*, Yinong Wang, George Tellides and Martin Bennett^*

From the Division of Cardiovascular Medicine,^* University of Cambridge Clinical School of Medicine Addenbrooke’s Centre for Clinical Investigation, Addenbrooke’s Hospital, Cambridge, United Kingdom; and the Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut

Vascular smooth muscle cell (VSMC) apoptosis occurs in advanced atherosclerotic plaques where it may contribute to plaque instability. VSMCs express the death receptor Fas but are relatively resistant to Fas-induced apoptosis due in part to the intracellular sequestration of Fas. Although inflammatory cytokines such as interferon (IFN)- present in plaques can prime VSMCs to FasL-induced death, the mechanism of this effect is unclear. We examined Fas expression and FasL-induced apoptosis in human VSMCs in response to IFN-. IFN- induced Fas trafficking to the cell surface within 24 hours, an effect that required Jak2/Stat1 activity. IFN- also stimulated Akt activity, and both Fas trafficking and Stat1 activation were inhibited by blocking PI3K, Akt, or Jak-2. IFN- increased Fas-induced apoptosis in vitro by 46 ± 8% (mean ± SEM, P = 0.04), an event that could be abrogated by inhibition of PI3K, Akt, or Jak-2. IFN- also increased Fas-induced apoptosis in vivo 7.5- to 15-fold (P < 0.05) in human arteries transplanted into immunodeficient mice, accompanied by increased Fas and phospho-Ser⁷²⁷-Stat1. We conclude that IFN- primes VSMCs to Fas-induced apoptosis, in part by relocation of Fas to the cell surface, a process that involves PI3K, Akt, and Jak-2/Stat1. IFN- present in plaques may co-operate with FasL to induce VSMC apoptosis in atherosclerosis.

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