title: HIF-regulated HO-1 gene transfer improves the post-ischemic limb recovery and diminishes TLR-triggered immune responses - Effects modified by concomitant VEGF overexpression.
abstract: Heme oxygenase-1 (HO-1) mitigates cellular injury by antioxidant, anti-apoptotic, anti-inflammatory and proangiogenic effects. Vascular endothelial growth factor (VEGF) is a critical regulator of blood vessel growth. Their coordinated action was analyzed in a model of femoral artery ligation (FAL) in mice lacking HO-1 gene (HO-1 KO). Gastrocnemius skeletal muscles of HO-1 KO mice were preemptively injected with plasmids containing hypoxia-response element (HRE) driving the expression of only HO-1 (pHRE-HO1) or both HO-1 and VEGF (pHRE-HO1-VEGF). At day 14th the pHRE-HO1 vector increased an impaired post-ischemic blood flow recovery in HO-1 KO mice to the level observed in wild-type (WT) mice subjected to FAL and pHRE-HO1-VEGF restored it already at day 7. The pHRE-HO1 gene therapy diminished, when compared to control pHRE-empty-treated HO-1 KO mice, the expression of toll-like receptors (TLR4 and TLR9) and inflammatory cytokines (IL-1β, IL-6 and TNFα) at day 3, whereas opposite effects were observed following concomitant HO-1 and VEGF gene transfer. Moreover, HO-1 diminished ischemia-induced expression of MyoD involved in satellite cell differentiation in HO-1 KO mice. Our results confirm the therapeutic potential of HO-1 and VEGF against critical limb ischemia although, their concomitant delivery may have contradictory actions on the resolution of inflammation.
authors: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. Electronic address: agnieszka.jazwa@uj.edu.pl.
authors: Agnieszka
authors: A
authors: Jazwa
authors: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors: Mateusz
authors: M
authors: Stoszko
authors: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors: Mateusz
authors: M
authors: Tomczyk
authors: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Department of Clinical Immunology and Transplantology, Polish-American Institute of Pediatrics, Medical College, Jagiellonian University, Krakow, Poland.
authors: Karolina
authors: K
authors: Bukowska-Strakova
authors: Centre de Biophysique Moleculaire, CNRS, Orleans, France; University of Orleans, Orleans, France.
authors: Chantal
authors: C
authors: Pichon
authors: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors: Alicja
authors: A
authors: Jozkowicz
authors: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
authors: Jozef
authors: J
authors: Dulak
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D051547:Heme Oxygenase-1 / Q000008:administration & dosage / Q000235:genetics*; D006614:Hindlimb / Q000098:blood supply; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000008:administration & dosage / Q000235:genetics*; D007111:Immunity, Cellular / Q000187:drug effects / Q000502:physiology*; D007511:Ischemia / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020127:Recovery of Function / Q000502:physiology; D051193:Toll-Like Receptors / Q000096:biosynthesis* / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051193:Toll-Like Receptors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
keywords: Gene therapy; HO-1; HRE; Inflammation; Regeneration; TLR; VEGF