HIF-1α Overexpression and Experimental Murine Atherosclerosis

• DOI: 10.1161/atvbaha.108.183319
• Publication Date: 2009-02-28T01:14:07Z
• Authors: Jeremy Ben-Shoshan; Arnon Afek; Sofia Maysel-Ausl...; Aya Barzelay; Ardon Rubinstein; Gad Keren; Jacob George
• Keywords: CD4-Positive T-Lymphocytes; Male; 0301 basic medicine; Atherosclerosis; Hypoxia-Inducible Factor 1, alpha Subunit; 3. Good health; Disease Models, Animal; Interferon-gamma; Mice; 03 medical and health sciences; Th2 Cells; Animals; Humans; Aorta; Cells, Cultured; Spleen

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.