Nature Medicine
6, 1004 - 1010 (2000)
doi:10.1038/79510
The HMG-CoA reductase inhibitor simvastatin activates the protein kinase
Akt and promotes angiogenesis in normocholesterolemic animals.Yasuko Kureishi1, Zhengyu Luo1, Ichiro Shiojima1, Ann Bialik1, David Fulton2, David J. Lefer3, William C. Sessa2
& Kenneth Walsh11
Division of Cardiovascular Research, St. Elizabeth's
Medical Center of Boston, and the Program in Cell, Molecular and Developmental
Biology, Sackler School of Biomedical Studies, Tufts University School of
Medicine, Boston, Massachusetts, 02135, USA
2
Department of Pharmacology and Molecular Cardiobiology
Program, Boyer Center for Molecular Medicine, Yale University School of Medicine,
New Haven, Connecticut, 06536, USA
3
Department of Molecular and Cellular Physiology, Louisiana
State University Health Sciences Center, Shreveport, Louisiana,
71130, USA
Correspondence should be addressed to Kenneth Walsh kwalsh@opal.tufts.edu or kwalsh@world.std.com
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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