Ablation of the Transcription Factor Nrf2 Promotes Ischemia-Induced Neovascularization by Enhancing the Inflammatory Response

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 30; no. 8; pp. 1553 - 1561
• Main Authors: Ichihara, Sahoko, Yamada, Yoshiji, Liu, Fang, Murohara, Toyoaki, Itoh, Ken, Yamamoto, Masayuki, Ichihara, Gaku
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.08.2010; Lippincott Williams & Wilkins
• Subjects: Acetylcysteine - pharmacology; Angiogenic Proteins - metabolism; Animals; Antioxidants - pharmacology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Capillaries - metabolism; Capillaries - physiopathology; Cardiology. Vascular system; Cell Adhesion Molecules - metabolism; Chemokine CCL2 - metabolism; Coronary heart disease; Cyclooxygenase 2 - metabolism; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - metabolism; Femoral Artery - surgery; Glutathione - metabolism; Heart; Heme Oxygenase-1 - metabolism; Hindlimb; Inflammation - genetics; Inflammation - metabolism; Inflammation - physiopathology; Inflammation Mediators - metabolism; Ischemia - genetics; Ischemia - metabolism; Ischemia - physiopathology; Laser-Doppler Flowmetry; Ligation; Male; Medical sciences; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal - blood supply; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - genetics; NF-E2-Related Factor 2 - deficiency; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidative Stress; Peroxiredoxins - metabolism; Regional Blood Flow; RNA, Messenger - metabolism; Superoxides - metabolism; Thioredoxins - metabolism; Time Factors; Tumor Necrosis Factor-alpha - metabolism; Vascular disease; Endothelial cell; endothelial cells; Ischemia; Atherosclerosis; Cardiovascular disease; Inflammation; Neovascularization; Transcription factor; Ablation; peripheral vascular disease
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.110.204123

OBJECTIVE—To investigate the potential role of nuclear factor–erythroid 2–related factor 2 (Nrf2) in neovascularization with a murine surgical model of ischemia. METHODS AND RESULTS—The transcription factor Nrf2 protects against oxidative stress by increasing the transcription of genes, including those for several antioxidant enzymes that contain an antioxidant response element. Ischemia was induced by femoral artery ligation in Nrf2-deficient (Nrf2) and wild-type mice. Ischemia-induced neovascularization was enhanced in Nrf2 mice compared with that in wild-type mice. The expression of Nrf2 target genes for heme oxygenase 1 and thioredoxin 1 and the concentration of total glutathione in the ischemic hindlimb were reduced for Nrf2 mice compared with wild-type mice. The infiltration of inflammatory cells and the abundance of adhesion molecule mRNA were greater in the ischemic hindlimb of Nrf2 mice than in wild-type mice. The expression of monocyte chemoattractant protein-1, tumor necrosis factor-α, cyclooxygenase 2, and angiogenic factors in the ischemic hindlimb was also greater for Nrf2 mice than for wild-type mice. CONCLUSION—The ablation of Nrf2 promoted ischemia-induced neovascularization. This effect likely resulted from impaired antioxidant defense and increased accumulation of reactive oxygen species in endothelial cells; consequently, there was an enhanced inflammatory response.