Statin therapy and angiogenesis.
OBJECTIVE
Clinical studies suggested that 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy has an additional cardiovascular protective activity that may function independently of the ability of statins to lower serum cholesterol. This paper reviews the available data on these effects and discusses the potential intracellular mechanisms involved.


RESULTS
Experimental studies have clearly shown that statins protect against ischaemia-reperfusion injury of the heart, and exert pro-angiogenic effects by stimulating the growth of new blood vessels in ischaemic limbs of normocholesterolemic animals. The mechanisms underlying these serum lipid-independent statin effects are not completely understood, but there is increasing evidence that statins improve endothelial function through molecular mechanisms that mediate an increase in endothelium-derived nitric oxide. Recent research has revealed a link between statins and the serine/threonine protein kinase Akt that regulates multiple angiogenic processes in endothelial cells. In contrast to these data, it has also been reported that higher doses of statins can inhibit endothelial cell migration and angiogenesis.


CONCLUSIONS
Statins have biphasic potential either to promote or inhibit angiogenesis. Low statin doses induce a pro-angiogenic effect through Akt activation and increase nitric oxide production, whereas high statin doses may decrease protein prenylation and inhibit cell growth. Notwithstanding, the clinical relevance of these serum lipid-independent effects is not fully understood. Further studies on the actions of statins on endothelial cells may lead to the identification of new pharmacological targets for the control of angiogenesis.
Skaletz-Rorowski
Adriane
A
Institute for Arteriosclerosis Research and Department of Cardiology and Angiology, University of Münster, Münster, Germany.
Walsh
Kenneth
K
D043924:Angiogenesis Modulating Agents / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008798:Mevalonic Acid / Q000378:metabolism; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D017368:Protein Prenylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D043924:Angiogenesis Modulating Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011518:Proto-Oncogene Proteins; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D008798:Mevalonic Acid