Abstract 5390: The Endothelial Nitric Oxide Synthase Enhancer AVE9488 Increases Circulating Endothelial Progenitor Cells and Prevents Heart Failure Early after Myocardial Infarction
We studied the effects of AVE9488, a novel endothelial nitric oxide synthase (eNOS) expression enhancer on endothelial progenitor cells (EPC) mobilizing pathways in bone marrow, EPC function and impact on myocardial function and neovascularisation early after myocardial infarction (MI). Male rats were treated with 25ppm AVE9488 starting immediately post- MI versus placebo. EPC number was assessed using fluorescence activated cell sorting, migratory capacity using modified Boyden chambers, neovascularisation by immunohistochemistry and cardiac function using echocardiography. Circulating EPC numbers were 5.2-fold (p<0.001) and migratory capacity 2.9-fold (p=0.03) increased after AVE9488 treatment when compared to placebo-treated animals after myocardial infarction. eNOS expression and activity was elevated by AVE9488 in bone marrow of myocardial infarction rats and positively correlated to EPC levels. In contrast, AVE9488 treatment prevented the increase of malondialdehyde, an indicator of reactive oxygen species production, in bone marrow extracts after myocardial infarction. Vascular endothelial growth factor (VEGF) expression in bone marrow was increased 1.6-fold (p<0.05) by AVE9488 versus placebo whereas plasma VEGF levels remained unchanged. In contrast, bone marrow matrix metallopeptidase 9 (MMP-9) activity was not affected by AVE9488. Elevated EPC levels were correlated improved neovascularisation in the peri-infarct region and with improved cardiac function (ejection fraction was increased by 29%, p<0.05) seven days after AVE9488 treatment. Treatment with the eNOS enhancer AVE9488 increased eNOS expression and activity in bone marrow early after MI with a subsequent marked increase in circulating EPC levels and improvement of myocardial function. Pharmacological interventions addressed to increase eNOS-derived NO in the bone marrow are a promising therapeutic approach to improve EPC number and function especially after myocardial infarction.