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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:665.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

HIF-1 Overexpression and Experimental Murine Atherosclerosis

Jeremy Ben-Shoshan; Arnon Afek; Sofia Maysel-Auslender; Aya Barzelay; Ardon Rubinstein; Gad Keren; Jacob George

From the Department of Cardiology (J.B.-S., S.M.-A., A.B., G.K.), Tel Aviv Sourasky Medical Center, Israel; the Department of Pathology (A.A.), Sheba Medical Center, Tel-Hashomer, Israel; the Sackler School of Medicine (J.B.-S., A.A., S.M.-A., A.B., G.K., J.G.), Tel Aviv University, Israel; and the Lipid Metabolic Unit (A.R.), Tel Aviv Sourasky Medical Center, Israel.

Correspondence to Jacob George, MD, Department of Cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. E-mail jacobg{at}post.tau.ac.il

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-1 in ApoE knockout murine lymphocytes, on experimental atherosclerosis.

Methods and Results— ApoE^–/– mice were submitted to intravenous hydrodynamic injection of empty plasmid or HIF-1P564A (HIF-1 mutated stabilized construct). Robust expression of HIF-1 was evident in spleen cells of recipient animals. Increased expression of IL-10 as well as decreased expression of IFN- was measured in splenocytes of HIF-1–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-1 injected mice. A reduced expression of IFN- was evident in CD4+ spleen-derived lymphocytes and aortas of HIF-1–injected mice.

Conclusions— HIF-1 expression in mouse lymphocytes is associated with a reduced IFN- expression and attenuation of experimental atherosclerosis.

We used a HIF-1 plasmid delivered by hydrodynamic injection to assess the effects on cellular immunity and atherosclerotic plaque size in ApoE^–/– mice. HIF-1 plasmid was expressed predominantly in CD4 cells and shifted their phenotype to the T_H2 lineage concomitantly with a significant reduction in atherosclerotic plaque size.

Key Words: atherosclerosis • cytokines • immune system • hypoxia-inducible factor-1 • T lymphocytes