on February 26, 2009
Published online before print February 26, 2009, doi: 10.1161/ATVBAHA.108.183319
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Submitted on August 19, 2008
Accepted on January 25, 2009
HIF-1
Overexpression and Experimental Murine Atherosclerosis
Jeremy Ben-Shoshan ;
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.
* To whom correspondence should be addressed. 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-alpha 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.