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The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.

An Erratum to this article was published on 01 January 2001

Abstract

Recent studies suggest that statins can function to protect the vasculature in a manner that is independent of their lipid-lowering activity. We show here that statins rapidly activate the protein kinase Akt/PKB in endothelial cells. Accordingly, simvastatin enhanced phosphorylation of the endogenous Akt substrate endothelial nitric oxide synthase (eNOS), inhibited apoptosis and accelerated vascular structure formation in vitro in an Akt-dependent manner. Similar to vascular endothelial growth factor (VEGF) treatment, both simvastatin administration and enhanced Akt signaling in the endothelium promoted angiogenesis in ischemic limbs of normocholesterolemic rabbits. Therefore, activation of Akt represents a mechanism that can account for some of the beneficial side effects of statins, including the promotion of new blood vessel growth.

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Figure 1: Statins promote Akt phosphorylation in endothelial cells.
Figure 2: Simvastatin stimulates Akt protein kinase activity.
Figure 3: Simvastatin induces Akt-mediated phosphorylation of eNOS in intact cells.
Figure 4: Simvastatin promotes endothelial cell survival through an Akt-dependent pathway.
Figure 5: Statins promote vascular structure formation in an in vitro Matrigel assay.
Figure 6: Statin administration or enhanced Akt signaling in endothelial cells promotes blood vessel formation in the rabbit hindlimb in response to unilateral femoral artery resection.

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Acknowledgements

This work was support by National Institutes of Health grants RO1-AR40197, RO1-HL50692, RO1-AG15052 and PO1-HD23681 to K.W. We thank Neil Tritman for supplying the human vascular cells.

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Correspondence to Kenneth Walsh.

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Kureishi, Y., Luo, Z., Shiojima, I. et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.. Nat Med 6, 1004–1010 (2000). https://doi.org/10.1038/79510

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