Abstract 18064: Heme Oxygenase-1 Induces Neovascularization After Myocardial Infarction Through Angiogenic Cytokines
Heme oxygenase-1 (HO-1) is known for its cytoprotective and anti-apoptotic function that protects against cardiac remodeling after myocardial infarction (MI). HO-1 is also known to enhance angiogenesis but the mechanism is still poorly understood. We assessed the hypothesis that HO-1 increases neovascularization by modulating the expression of cytokines and growth factors. In our experiment male Wistar rats were given Cobolt Protoporphyrin IX (CoPPIX, 5 mg/kg, ip, −24h, n=60) to induce HO−1. Control rats received no pretreatment (n=60). Rats were subjected to LAD ligation or sham-operation and sacrificed at 1, 3, 7 or 28 days after LAD ligation. Capillary and vascular densities were assessed by immunofluorescent microscopy. Real-time RT-PCR array and western blot analyses were performed to examine the expression of angiogenic factors. HO-1 induction significantly increased both capillary (161±29/mm2 vs. 70±10/mm2, p=0.004) and vascular (446±26/mm2 vs. 306±25/mm2, p=0.04) densities in the infarct area at week 4 compared to control hearts. The PCR array analysis showed that HO-1 induction significantly upregulated the expression of several angiogenic factors, including HIF-1a, IGF-1, IL-6, MCP-1, NRP-1, NRP-2, Plgf and VEGFD compared to control infarct hearts at day three (p<0.05). We also observed an elevated trend in VEGF-B (2.73-fold, p=0.27) and VEGFR-2 (1.97-fold, p=0.511) at day 28. In Western blot analysis HO-1 induction increased plgf protein levels 2-fold at week 1 (1.57±0.31 vs. 0.78±0.16, p=0.04, n=6 per group) and 1.66-fold at week 4 (1.61±0.19 vs. 0.97±0.12, p=0.02 n=5 per group) post MI. There was an elevated trend in VEGFA protein level at day 28 which increased 2-fold (1.84±0.45 vs. 0.90±0.10, p=0.30, n=3 per group). In conclusion, HO-1 induction significantly promoted neovascularization in the infarcted hearts by inducing the expression of VEGF family members and several other angiogenic factors. As a novel finding, HO-1 upregulated gene expression and protein levels of Plgf. HO-1 may provide a new mechanism to enhance neovascularization after myocardial infarction.
- © 2010 by American Heart Association, Inc.