Abstract 486: Targeting Bone Marrow Endothelial Nitric Oxide Synthase (eNOS) by the eNOS Enhancer AVE9488 Increases Circulating Endothelial Progenitor Cells After Myocardial Infarction
Endothelial progenitor cells (EPCs) play a major role in neoangiogenesis after myocardial infarction (MI). EPCs are located in a microenvironment of bone marrow stromal and endothelial cells, and are translocated to the circulation upon matrix metalloproteinase-9 (MMP-9) and/or vascular endothelial growth factor (VEGF)/nitric oxide (NO) mediated pathways. We studied the effects of AVE9488, a novel eNOS expression enhancer, on EPC mobilising pathways in bone marrow early after MI. Treatment with AVE9488 (25ppm, for 3 days starting immediately post-MI) versus placebo increased levels of circulating EPC 5.2-fold (p<0.001). eNOS expression (0.726±0.06 versus 0.403±0.05 densitometric units/μg protein, p<0.05) and activity (20.4±4.4 versus 7.15±0.9 nmol/μg protein x103, p<0.05) were increased by AVE9488 in bone marrow of MI rats. VEGF expression in bone marrow was increased by AVE9488 versus placebo MI rats (0.121±0.01 versus 0.076±0.01 pg/μg protein, p<0.05), whereas plasma VEGF levels were unchanged. Phosphorylation of Akt1 in bone marrow was significantly increased in AVE9488-treated animals (0.519±0.09 versus 0.310±0.09 densitometric units/μg protein, p<0.05), whereas malondialdehyde, an index of reactive oxygen species formation, was reduced (0.560±0.12 versus 1.362±0.30 μmol/μg protein, p<0.05). MMP-9 activity was not affected by AVE9488 (448±36 versus 438±82 densitometric units/μg protein). Treatment with the eNOS enhancer AVE9488 reduced ROS formation and increased eNOS expression and activity in rat bone marrow early after MI with a subsequent marked increase in circulating EPC levels. Thus, the eNOS enhancer AVE9488 is an interesting novel approach for post-MI treatment.