Pravastatin accelerates ischemia-induced angiogenesis through AMP-activated protein kinase
Open Access
- 5 June 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Hypertension Research
- Vol. 32 (8), 675-679
- https://doi.org/10.1038/hr.2009.77
Abstract
Statins exert pleiotropic effects on the cardiovascular system, in part through an increase in nitric oxide (NO) bioavailability. In this study, we examined the role of pravastatin in ischemia-induced angiogenesis. Unilateral hindlimb ischemia was surgically induced in C57BL/6J mice. Phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC) and endothelial NO synthase (eNOS) was increased in ischemic tissues. Furthermore, mice treated with pravastatin showed higher increases in phosphorylation than did untreated mice. Laser Doppler analysis has shown that pravastatin treatment accelerates the development of collateral vessels and angiogenesis in response to hindlimb ischemia. Capillary density in the ischemic hindlimb was also increased by pravastatin treatment. An in vitro study on human umbilical vein endothelial cells (HUVECs) revealed that pravastatin increased the phosphorylation of AMPK. Pravastatin-induced phosphorylation of eNOS, one of the downstreams of AMPK, was inhibited by compound C, an AMPK antagonist. The increased migration and tube formation of HUVECs by pravastatin were significantly blocked by compound C treatment. The accelerated angiogenesis by pravastatin after hindlimb ischemia was significantly reduced after treatment with compound C. Thus, ischemia induced AMPK phosphorylation in vivo. Furthermore, pravastatin could also activate AMPK in vivo and in vitro. Such phosphorylation results in eNOS activation and angiogenesis, which provide a novel explanation for one of the pleiotropic effects of statins that is beneficial for angiogenesis.Keywords
This publication has 36 references indexed in Scilit:
- AMP-Activated Protein Kinase Functionally Phosphorylates Endothelial Nitric Oxide Synthase Ser633Circulation Research, 2009
- AMPK regulates basal skeletal muscle capillarization and VEGF expression, but is not necessary for the angiogenic response to exerciseThe Journal of Physiology, 2008
- AMP‐ACTIVATED PROTEIN KINASE ACTIVATION AS A STRATEGY FOR PROTECTING VASCULAR ENDOTHELIAL FUNCTIONClinical and Experimental Pharmacology and Physiology, 2007
- Metformin Inhibits Cytokine-Induced Nuclear Factor κB Activation Via AMP-Activated Protein Kinase Activation in Vascular Endothelial CellsHypertension, 2006
- Estradiol-Mediated Endothelial Nitric Oxide Synthase Association With Heat Shock Protein 90 Requires Adenosine Monophosphate-Dependent Protein KinaseCirculation, 2005
- AMP-Activated Protein Kinase Signaling Stimulates VEGF Expression and Angiogenesis in Skeletal MuscleCirculation Research, 2005
- AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolismCell Metabolism, 2005
- Activation of Apoptosis Signal-Regulating Kinase 1 in Injured Artery and Its Critical Role in Neointimal HyperplasiaCirculation, 2003
- Endothelial nitric oxide synthase is essential for the HMG‐CoA reductase inhibitor cerivastatin to promote collateral growth in response to ischemiaThe FASEB Journal, 2001
- Neuroprotection mediated by changes in the endothelial actin cytoskeletonJCI Insight, 2000