Nrf2 gene transfer induces antioxidant enzymes and suppresses smooth muscle cell growth in vitro and reduces oxidative stress in rabbit aorta in vivo.
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.


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 beta-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.
Levonen
Anna-Liisa
AL
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. Anna-Liisa.Levonen@uku.fi
Inkala
Matias
M
Heikura
Tommi
T
Jauhiainen
Suvi
S
Jyrkkänen
Henna-Kaisa
HK
Kansanen
Emilia
E
Määttä
Kirsi
K
Romppanen
Elina
E
Turunen
Päivi
P
Rutanen
Juha
J
Ylä-Herttuala
Seppo
S
D000818:Animals; D001011:Aorta / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis; D001167:Arteritis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D002404:Catheterization / Q000009:adverse effects; D002455:Cell Division; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000503:physiopathology; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D017539:Tunica Intima / Q000473:pathology / Q000503:physiopathology
D051267:NF-E2-Related Factor 2; D010088:Oxidoreductases; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone)