Abstract 15636: Heme Oxygenase-1 is Necessary for Ischemia-Mediated Neovascularization
Objectives: Heme oxygenase-1 (HO-1), an enzyme traditionally known for its role in heme catabolism, may play a vascular protective role. We hypothesized that HO-1 plays a role in ischemia-mediated neovascularization, and that this may be mediated by bone marrow-derived progenitor cells (BMPC).
Methods: We studied the role HO-1 in three complementary models of murine hindlimb ischemia (HLI): 1) HO-1 knockout (KO) vs. wildtype (WT) mice; 2) a bone marrow transplant model where HO-1 KO or WT bone marrow were transplanted into WT recipient mice 1 day after irradiation, and 3) HO-1 overexpression by adenoviral-mediated gene therapy (108 pfu) in WT mice. Limb perfusion was assessed using laser-Doppler imaging. BMPCs were characterized by DilAcLDL+/BS-1 lectin+ staining.
Results: Compared with WT mice, HO-1 KO mice showed a complete absence of limb perfusion recovery after HLI (limb perfusion ratio at sacrifice of ischemic/non-ischemic limb 0.05±0.02 vs. 0.33±0.03; P<0.01), with a 100% amputation rate (vs. 0%; P=0.02), worse foot movement scores (3.0±0 vs.1.3±0.4; P<0.005), 2.8±1.0-fold reduction in capillary density (P=0.02), and reduced BMPC levels (76.8±15.8 vs.122.6±18.0; P<0.05). Transplantation of HO-1 KO marrow into WT mice was associated with markedly impaired limb perfusion recovery after HLI (0.11±0.04 vs. 0.31±0.06 for control WT; P=0.01), worse ischemia and foot movement scores (P<0.005) and reduced BMPC levels (92.2±18.4 vs.162.7±25.6 for control WT; P=0.03). Moreover, compared with placebo, HO-1 gene transfer augmented HO-1 protein expression 1.9±0.2-fold at time of sacrifice, increased limb perfusion recovery after HLI in WT mice (0.36±0.1 vs. 0.29±0.1; P for trend <0.01), and improved ischemia and foot movement scores (P<0.01).
Conclusion: HO-1 is required for ischemia-mediated neovascularization, likely via BMPC-mediated angiogenesis, and the absence of HO-1 resulted in a complete lack of limb perfusion recovery and 100% amputation rate after HLI. These data suggest a role for modulation of HO-1 activity in therapeutic angiogenesis.
- © 2011 by American Heart Association, Inc.