Effects of statins on endothelium and signaling mechanisms.
Endothelium dysfunction may result from increased production of reactive oxygen species and decreased availability of nitric oxide. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (ie, statins) exert cholesterol-independent vasoprotective effects that are mediated, in part, through the inhibition of small G-proteins Rho and Rac. Rho negatively regulates endothelial nitric oxide synthase and Rac contributes to NAD(P)H-oxidase activation and superoxide production. Statins inhibit both Rho and Rac GTPase activity via inhibition of geranylgeranylation, which confers endothelial nitric oxide synthase upregulation and decreases superoxide production, respectively. Sudden discontinuation of statin therapy may have negative effects. Withdrawal of statin treatment leads to an overshoot activation of Rho and Rac with dramatic effects on nitric oxide bioavailability, NAD(P)H-oxidase activity, and superoxide production.
Endres
Matthias
M
Klinik und Poliklinik für Neurologie, Charité-Universitätsmedizin Berlin, Campus Mitte, Schumannstr 20/21, 10117 Berlin, Germany. Matthias.endres@charite.de
Laufs
Ulrich
U
D004730:Endothelium, Vascular / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D019255:NADPH Oxidases; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D015398:Signal Transduction; D013375:Substance Withdrawal Syndrome; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein