HIF-1α overexpression and experimental murine atherosclerosis

BACKGROUND-: Lymphocytes play an important role in the progression of atherosclerosis. Recently, hypoxia inducible factor-1 (HIF-1) was found to attenuate inflammation by regulating T cell activation and cytokine production. We studied the effects of overexpression of HIF-1α in ApoE knockout murine lymphocytes, on experimental atherosclerosis. METHODS AND RESULTS-: ApoE mice were submitted to intravenous hydrodynamic injection of empty plasmid or HIF-1αP564A (HIF-1α mutated stabilized construct). Robust expression of HIF-1α was evident in spleen cells of recipient animals. Increased expression of IL-10 as well as decreased expression of IFN-γ was measured in splenocytes of HIF-1α-treated mice by RT-PCR. One week postinjection, antibody array analysis revealed a pattern consistent with a T helper 1 to T helper 2 shift. On sacrifice, assessment of aortic sinus lesions revealed a significant reduction in plaque size in HIF-1α injected mice. A reduced expression of IFN-γ was evident in CD4+ spleen-derived lymphocytes and aortas of HIF-1α-injected mice. CONCLUSIONS-: HIF-1α expression in mouse lymphocytes is associated with a reduced IFN-γ expression and attenuation of experimental atherosclerosis.