Beraprost sodium enhances neovascularization in ischemic myocardium by mobilizing bone marrow cells in rats Yoshinori Miyahara a , Shunsuke Ohnishi a , Hiroaki Obata a , Kozo Ishino b , Shunji Sano b , Hidezo Mori c , Kenji Kangawa d , Soichiro Kitamura e , Noritoshi Nagaya a, * a Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Osaka, Japan b Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan c Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Osaka, Japan d Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka, Japan e Department of Cardiovascular Surgery, National Cardiovascular Center, Osaka, Japan Received 13 August 2006 Available online 7 September 2006 Abstract Beraprost sodium, an orally active prostacyclin analogue, has vasoprotective effects such as vasodilation and antiplatelet activities. We investigated the therapeutic potential of beraprost for myocardial ischemia. Immediately after coronary ligation of Sprague–Dawley rats, beraprost (200 lg/kg/day) or saline was subcutaneously administered for 28 days. Four weeks after coronary ligation, administra- tion of beraprost increased capillary density in ischemic myocardium, decreased infarct size, and improved cardiac function in rats with myocardial infarction. Beraprost markedly increased the number of CD34-positive cells and c-kit-positive cells in plasma. Also, four weeks after coronary ligation of chimeric rats with GFP-expressing bone marrow, bone marrow-derived cells were incorporated into the infarcted region and its border zone. Treatment with beraprost increased the number of GFP/von Willebrand factor-double-positive cells in the ischemic myocardium. These results suggest that beraprost has beneficial effects on ischemic myocardium partly by its ability to enhance neovascularization in ischemic myocardium by mobilizing bone marrow cells. Ó 2006 Elsevier Inc. All rights reserved. Keywords: Prostacyclin analogue; Myocardial infarction; Neovascularization; Bone marrow mobilization Interruption of myocardial blood flow leads to rapid death of cardiomyocytes and vascular structures, resulting in the development of heart failure [1]. Stem or progenitor cells are mobilized from bone marrow into the peripheral blood in response to tissue ischemia, migrate to sites of injured tissues, and differentiate into endothelial cells and cardiomyocytes [2–4]. However, the compensatory mecha- nisms are insufficient to heal infarcted myocardium. Earlier studies have shown that bone marrow cells artificially mobilized by cytokines repair the infarcted heart and improve cardiac function after acute myocardial infarction [5,6]. Therefore, enhancement of bone marrow cell mobili- zation leading to neovascularization following revasculari- zation would be beneficial for the treatment of acute myocardial infarction. Beraprost sodium (BPS) is a chemically stable prostacy- clin analogue owing to its cyclo-pentabenzofuranyl struc- ture [7]. It has been well established that BPS has vasoprotective effects such as vasodilation and antiplatelet activities [8–11]. Thus, BPS has been used in the treatment of peripheral arterial disease [12,13] and pulmonary arterial hypertension [14,15]. Although a limited number of studies suggest therapeutic potential of prostacyclin for the treat- ment of myocardial ischemia [16–18], the underlying mech- anisms still remain unclear. In addition, little information is available regarding the therapeutic potential of prostacy- clin analogues such as BPS for myocardial ischemia. A recent study has shown that BPS activates endothelial 0006-291X/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2006.08.178 * Corresponding author. Fax: +81 6 6833 9865. E-mail address: nnagaya@ri.ncvc.go.jp (N. Nagaya). www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 349 (2006) 1242–1249 BBRC