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-1 beta, IL-6 and TNF alpha) 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.
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https://hal.archives-ouvertes.fr/hal-02072271
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Submitted on : Tuesday, March 19, 2019 - 9:06:17 AM
Last modification on : Friday, May 24, 2019 - 11:36:03 AM

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Agnieszka Jazwa, Mateusz Stoszko, Mateusz Tomczyk, Karolina Bukowska-Strakova, Chantal Pichon, et al.. HIF-regulated HO-1 gene transfer improves the post-ischemic limb recovery and diminishes TLR-triggered immune responses — Effects modified by concomitant VEGF overexpression. Vascular Pharmacology, Elsevier, 2015, 71, pp.127-138. ⟨10.1016/j.vph.2015.02.011⟩. ⟨hal-02072271⟩

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