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Abstract
Endothelial progenitor cells (EPCs) have been isolated from circulating mononuclear cells in peripheral blood and shown to incorporate into foci of neovascularization, consistent with postnatal vasculogenesis. These circulating EPCs are derived from bone marrow and are mobilized endogenously in response to tissue ischemia or exogenously by cytokine stimulation. We show here, using a chemotaxis assay of bone marrow mononuclear cells in vitro and EPC culture assay of peripheral blood from simvastatin-treated animals in vivo, that the HMG-CoA reductase inhibitor, simvastatin, augments the circulating population of EPCs. Direct evidence that this increased pool of circulating EPCs originates from bone marrow and may enhance neovascularization was demonstrated in simvastatin-treated mice transplanted with bone marrow from transgenic donors expressing β-galactosidase transcriptionally regulated by the endothelial cell-specific Tie-2 promoter. The role of Akt signaling in mediating effects of statin on EPCs is suggested by the observation that simvastatin rapidly activates Akt protein kinase in EPCs, enhancing proliferative and migratory activities and cell survival. Furthermore, dominant negative Akt overexpression leads to functional blocking of EPC bioactivity. These findings establish that augmented mobilization of bone marrow–derived EPCs through stimulation of the Akt signaling pathway constitutes a novel function for HMG-CoA reductase inhibitors.
Authors
Joan Llevadot, Satoshi Murasawa, Yasuko Kureishi, Shigeki Uchida, Haruchika Masuda, Atsuhiko Kawamoto, Kenneth Walsh, Jeffrey M. Isner, Takayuki Asahara
Simvastatin Promotes Angiogenesis - and Tumor Growth?
Submitter: Zoltan Ungvari MD, PhD and Pal Pacher MD, PhD | zoltan_ungvari@nymc.edu
New York Medical College Dept of Physiology/INOTEK Corporation, Beverly MA
Published October 19, 2001
In the August 2001 issue of The Journal of Clinical Investigation Llevadot et al1 reported that the HMG-CoA reductase inhibitor simvastatin promotes the mobilization of bone marrow-derived endothelial progenitor cells and thus may promote angiogenesis. These findings are supported by the result of a recent study published in Nature Medicine showing that simvastatin augment angiogenesis - similar to vascular endothelial growth factor (VEGF) - by activation of a protein kinase Akt-nitric oxide synthase dependent pathway in endothelial cells2. The authors of both studies suggest that angiogenic effect of simvastatin may be clinically relevant in the treatment of ischemic heart disease. However, there is no evidence that chronic simvastatin treatment-induced angiogenesis will be localized only in the heart. Since the original observation of Judah Folkman3 it has become clear that angiogenesis is a key factor for the growth of solid tumors. Thus, one can assume that systemic induction of angiogenesis by a drug that is widely prescribed to elderly patients - who are at risk of having latent neoplasms - has the potential to promote tumor growth. It should also be noted that nitric oxide synthesis -which is known to be upregulated by simvastatin4 - is believed to be involved in tumor angiogenesis5. In the light of the recent decision (August 7, 2001) of Bayer Corporation to halt the production of Baycol (cerivastatin) one should always keep in mind that statin therapy may have serious unexpected adverse effects. The potential contribution of the recently observed angiogenic effect of simvastatin to its therapeutic and/or side effects is an important issue that requires further evaluation.
1. Llevadot, J., et al. 2001. HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest. 108:399-405.
2. Kureishi, Y., et al. 2000. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 6:1004-10.
3. Folkman, J., et al. 1971. Isolation of a tumor factor responsible or angiogenesis. J Exp Med.133:275-88.
4. Mital, S., et al. 2000. Simvastatin upregulates coronary vascular endothelial nitric oxide production in conscious dogs. Am J Physiol Heart Circ Physiol. 279:H2649-57.
5. Jadeski, L.C. and Lala, P.K. 1999. Nitric oxide synthase inhibition by N(G)-nitro-L-arginine methyl ester inhibits tumor-induced angiogenesis in mammary tumors. Am J Pathol. 155:1381-90.
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