Bone marrow molecular alterations after myocardial infarction: Impact on endothelial progenitor cells

Objective: Standard drugs post-myocardial infarction (MI) such as angiotensin converting enzyme (ACE) and 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors (statins) increase levels of endothelial progenitor cells (EPC). However, potential underlying mechanisms have not yet been investigated. Methods and results: We studied the effects of ACE inhibition or statin treatment on EPC levels and on bone marrow molecular pathways involved in EPC mobilization after MI in rats. Three days post-infarction, acetylated LDL (acLDL)(+)/Ulex europeus-1 (UEA-1)(+)/VEGF receptor-2(+)/eNOS(+)EPC levels and formation of endothelial colony forming units (CFU) were reduced to 60 +/- 12% (p < 0.05) and 68 +/- 7% (p < 0.05). In bone marrow, extracellular signal-regulated kinase (ERK) phosphorylation and matrix metal loproteinase (MMP)-9 activity were repressed. Endothelial nitric oxide synthase (eNOS) activity was unchanged, whereas reactive oxygen species (ROS) were increased two-fold in bone marrow. ACE or HMG-CoA reductase inhibition resulted in significant increases in EPC levels. ACE inhibition increased bone marrow ERK phosphorylation and MMP-9 activity. Statin therapy enhanced bone marrow VEGF protein levels, Akt phosphorylation, eNOS activity and normalized increased ROS levels. Augmented EPC levels in the early post-infarction phase by ACE inhibition or statin treatment were associated with improved cardiac function and increased capillary density in the peri-infarct area 7 days after MI. Moreover, increased EPC levels in response to ACE inhibition or statin treatment were sustained 10 weeks post-infarction. Conclusions: Increased ROS and impaired MMP-9 activity in bone marrow likely contribute to reduced EPC mobilization in the early post-infarction phase. ACE inhibition or statin treatment increased EPC levels with distinct drug-specific effects on bone marrow molecular alterations. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.