on October 11, 2007
Published online before print October 11, 2007, doi: 10.1161/ATVBAHA.107.151050
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Submitted on March 5, 2007
Accepted on August 30, 2007
Expression of HIF-1
in Injured Arteries Controls SDF-1–Mediated Neointima Formation in Apolipoprotein E–Deficient Mice
Ela Karshovska ;
From the Division of Cardiology (E.K., G.S., A.M., F.K., H.-Y.S., V.K., A.S.), Medizinische Poliklinik, University of Munich; Division of Nephrology (C.C., H.S.), Medizinische Poliklinik, University of Munich; and Institute of Molecular Cardiovascular Research (IMCAR) (A.Z., M.H., C.W.), University Hospital Aachen, Germany.
* To whom correspondence should be addressed. E-mail: andreas.schober{at}med.uni-muenchen.de.
Objective—Hypoxia-inducible factor (HIF)-1
is the regulatory subunit of a transcriptional complex, which controls the recruitment of multipotent progenitor cells and tissue repair in ischemic tissue by inducing stromal cell-derived factor (SDF)-1 expression. Because HIF-1 can be activated under normoxic conditions in smooth muscle cells (SMCs) by platelet products, we investigated the role of HIF-1 in SDF-1–mediated neointima formation after vascular injury.
Methods and Results—Wire-induced injury of the left carotid artery was performed in apolipoprotein E–deficient mice. HIF-1 expression was increased in the media as early as 1 day after injury, predominantly in SMCs. Nuclear translocation of HIF-1 and colocalization with SDF-1 was detected in neointimal cells after 2 weeks. HIF-1 mRNA expression was induced at 6 hours after injury as determined by real-time RT-PCR. Inhibition of HIF-1 expression by local application of HIF-1-siRNA reduced the neointimal area by 49% and significantly decreased the neointimal SMCs content compared with control-siRNA. HIF-1 and SDF-1 expression was clearly diminished in neointimal cells of HIF-1-siRNA treated arteries.
Conclusions—HIF-1 expression is directly involved in neointimal formation after vascular injury and mediates the upregulation of SDF-1, which may affect the stem cell–based repair of injured arteries.
Key words: atherosclerosis • restenosis • vascular biology • chemokines • progenitor cells • smooth muscle cells
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