O38	Bone marrow molecular alterations after myocardial infarction: impact on endothelial progenitor cells and modulation by ACE inhibition or statin treatment.
1T.Thum, 1D.Fraccarollo, 1P.Galuppo, 2D.Tsikas, 1S.Froese, 1S.Frantz, 1G.Ertl, 1J.Bauersachs
1Julius-Maximilians-Universität, Würzburg, DE; 2Institut für Klinische Pharmakologie, Hannover, DE.

Objectives- Increased circulating endothelial progenitor cells (EPC) have been reported after myocardial infarction (MI). However, it is unclear whether ischemia or concomitant medication is the main stimulus for EPC mobilisation. In addition, analyses of molecular alterations in bone marrow after MI are lacking. Methods and Results- We studied circulating EPC levels and molecular changes in bone marrow three days and 10 weeks after large MI in rats. We focused on vascular endothelial growth factor (VEGF)/nitric oxide (NO) and extracellular signal-regulated kinase (ERK)/matrix metalloproteinase-9 (MMP-9) mediated pathways which are involved in EPC mobilisation from bone marrow. Circulating levels of acetylated LDL+/Ulex europeus-1+/VEGF receptor-2+/eNOS+ EPC were reduced to 60±12% (p<0.05) 3 days after MI. In bone marrow, ERK phosphorylation and MMP-9 activity were repressed after MI. Endothelial nitric oxide synthase (eNOS) expression and activity was unchanged, whereas reactive oxygen species (ROS) in bone marrow were increased 2-fold. Angiotensin-converting-enzyme (ACE) or 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibition resulted in 3- and 5-fold increases in EPC levels. ACE inhibition increased bone marrow phosphorylated ERK protein levels and MMP-9 activity independently from eNOS activity. Statin therapy enhanced VEGF protein expression, Akt phosphorylation, eNOS activity and normalised increased ROS levels, but did not affect ERK phosphorylation and MMP-9 activity. Conclusions- Circulating EPC levels are reduced in rats after MI associated with increased ROS, reduced ERK phosphorylation and MMP-9 activity in bone marrow. ACE inhibition or statin treatment increased circulating EPC with distinct drug-specific effects on bone marrow molecular alterations.

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