Abstract 1211: Hif-1α In T Cells Pathway Plays A Crucial Role In The Progression Of Arteriosclerosis And Artery Intimal Thickening
Background and Objective T cell-mediated inflammatory process is involved in arteriosclerosis and vascular remodeling. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor and regulates the gene expressions in response to hypoxia in order to maintain physiological oxygen homeostasis. In the previous annual meeting, we showed that arterial cuff injury caused prominent neointimal and adventitial hyperplasia in Hif-1α-deficient mice compared to that of the control mice. The object of the present study is to reveal how the function of HIF-1α in T cells contributes to the vascular remodeling.
Methods and Results T cell-specific Hif-1α-deficient mice were generated using a Cre-LoxP technology. Vascular remodeling was characterized 4 weeks after femoral arterial injury induced by an external vascular polyethylene cuff model. Morphological and histological studies showed that the cuff placement caused prominent neointimal and adventitial hyperplasia in Hif-1α-deficient mice compared to that of the control mice, and that infiltration of mononuclear cells at the adventitia was remarkably increased in the mutant mice. Hif-1α-deficient T cells were normally generated in the thymus and their distribution in the spleen and lymph nodes was unimpaired. However, number of peripheral Hif-1α-deficient T cells was significantly increased compared to the control. In the in vitro culture condition, Hif-1α-deficient T cells exhibited significant more increases of IL2 production and proliferation upon stimulation with anti-CD3/anti-CD28 antibodies compared to the controls. In addition, productions of 2,4,6-trinitrophenol (TNP)-KLH antigen-specific antibodies, including IgG1, IgG2b and IgG2c, were more enhanced in the mutant mice after stimulation of the antigen.
Conclusions HIF-1α in T cells plays a crucial role in vascular inflammation and remodeling in response to cuff injury, serving as a negative regulator of T cell-mediated immune response.