on January 25, 2007
Published online before print January 25, 2007, doi: 10.1161/01.ATV.0000258868.80079.4d
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Submitted on April 25, 2006
Accepted on January 9, 2007
Nrf2 Gene Transfer Induces Antioxidant Enzymes and Suppresses Smooth Muscle Cell Growth In Vitro and Reduces Oxidative Stress in Rabbit Aorta In Vivo
Anna-Liisa Levonen *;
From the Departments of Biotechnology and Molecular Medicine (A.-L.L., M.I., T.H., S.J., H.-K.J., E.K., K.M., E.R., P.T., J.R., S.Y.-H.), A.I. Virtanen Institute, Kuopio University; Department of Medicine, Kuopio University (S.Y.-H.); and Gene Therapy Unit, Kuopio University Hospital (S.Y.-H.), Kuopio, Finland.
* To whom correspondence should be addressed. E-mail: Anna-Liisa.Levonen{at}uku.fi.
Background--Reactive oxygen species (ROS) play a major role in vascular inflammation and pathophysiology of many vascular diseases such as atherosclerosis and injury-induced neointima formation after balloon angioplasty. Nuclear factor E2-related factor-2 (Nrf2) is a transcription factor orchestrating antioxidant and cytoprotective responses on oxidative and electrophilic stress, and it has been shown to have antiinflammatory effects in vascular cells in vitro. We therefore postulated that Nrf2 gene transfer would have salutary effects on vascular inflammation after angioplasty.
Methods and Results--Transduction of vascular smooth muscle cells (VSMCs) with Nrf2-expressing adenovirus increased the expression of several antioxidant enzymes including heme oxygenase-1 (HO-1) compared with 
-galactosidase (AdLacZ)-transduced controls. Moreover, Nrf2 gene transfer also inhibited vascular smooth muscle cell (VSMC) proliferation, and the effect was partially reversed by the HO inhibitor Sn(IV) protoporphyrin. In vivo, adenoviral gene transfer effectively reduced oxidative stress determined by antibody staining against oxidized epitopes of LDL, as well as inhibited vascular inflammation assessed by the macrophage cell count and monocyte chemoattractant protein-1 (MCP-1) staining. However, the antiproliferative effects of Nrf2 in vivo were counterbalanced with diminished apoptosis in neointimal VSMCs, resulting in no change in neointimal hyperplasia.
Conclusions--Nrf2 gene transfer or Nrf2-inducing drugs may have therapeutic applications in vascular diseases in which inflammation and oxidative stress play a role. However, the contrasting growth inhibitory and antiapoptotic effects of Nrf2 need to be considered in pathological conditions in which SMC proliferation plays a critical role.
Key words: angioplasty • antioxidants • free radicals • gene therapy • restenosis
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