Antiatherosclerotic effects of statins: LDL versus non-LDL effects.
Cardiovascular risk factors, particularly low-density lipoproteins (LDL), give rise to atherosclerosis and its complications by triggering a dysfunctional endothelium, inflammation, and a procoagulant vascular surface. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibition by statins leads to a fall in circulating and plaque LDL concentrations and improvement in many cellular dysfunctions, but controlled trials only show partial benefit with regard to myocardial infarction, stroke, and cardiovascular death. Emerging clinical evidence now shows that these risk factors also stimulate the activation (isoprenylation) of small G-binding proteins and, through their effectors (Rho-associated kinase) they can activate many or most of the subcellular and vessel wall pathophysiology of atherosclerosis. Inhibition of Rho-kinase can improve these dysfunctions with no changes in LDL. Similarly, statins can diminish the activation of these small G-binding proteins and their downstream effectors in atherosclerosis. This review compares and contrasts the effects of statins on atherosclerosis that are related to changes in LDL with those effects occurring through these alternate lipid pathways, and suggests that the therapeutic control of these small G-binding proteins and their downstream effectors may significantly add to the partial benefits of using statins in patients with atherosclerotic heart disease.
Selwyn
Andrew P
AP
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital & Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. aselwyn@partners.org
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects*; D002986:Clinical Trials as Topic; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy; D012307:Risk Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D054460:rho-Associated Kinases