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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:741.)
© 2007 American Heart Association, Inc.

Vascular Biology

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; Matias Inkala; Tommi Heikura; Suvi Jauhiainen; Henna-Kaisa Jyrkkänen; Emilia Kansanen; Kirsi Määttä; Elina Romppanen; Päivi Turunen; Juha Rutanen; Seppo Ylä-Herttuala

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.

Correspondence to Anna-Liisa Levonen, MD, PhD, Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, P.O. Box 1627 (street address: Neulaniementie 2) FIN-70211 Kuopio, Finland. 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 ß-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.

We studied the effect of gene transfer of Nrf2, a transcription factor regulating antioxidant genes on VSMC growth, oxidative stress, and inflammation. Nrf2 overexpression induced antioxidant genes and inhibited VSMC proliferation in vitro, and reduced oxidative stress in vivo determined by oxLDL and inflammation assessed by macrophage number.

Key Words: angioplasty • antioxidants • free radicals • gene therapy • restenosis

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