Adverse balance of nitric oxide/peroxynitrite in the dysfunctional endothelium can be reversed by statins.
Vascular endothelial dysfunction is a complex phenomenon that might be caused by a deficiency of nitric oxide (NO) and an overproduction of peroxynitrite (ONOO-). This study used a nanotechnological approach to monitor the in vitro effect of statins on the [NO]/[ONOO-] balance in normal and dysfunctional endothelial cells. NO and (ONOO-) were measured by electrochemical nanosensors in a single human umbilical vein endothelial cell (HUVEC) treated with atorvastatin or simvastatin for 24 hours in the presence or absence of 50 microg/mL oxidized-LDL. An imbalance between [NO]/[ONOO-] concentrations was used as an indicator of endothelial dysfunction and correlated with endothelial nitric oxide synthase (eNOS) expression. Ox-LDL induced dysfunction of the endothelium by uncoupling eNOS. NO concentration decreased from 300 +/- 12 to 146 +/- 8 nmol/L and (ONOO-) increased from 200 +/- 9 to 360 +/- 13 nmol/L. The [NO]/[ONOO-] balance decreased from 1.50 +/- 0.04 (control) to 0.40 +/- 0.03 for cells co-incubated with ox-LDL. Treatment with statins reversed eNOS uncoupling, induced by oxidized-LDL and significantly increased the [NO]/[ONOO-] balance to 1.2 +/- 0.1. These results demonstrate that statins can restore endothelial function by increasing eNOS expression, decreasing eNOS uncoupling, reducing the (ONOO-) level (nitroxidative stress), and shifting the [NO]/[ONOO-] balance towards NO.
Department of Biochemistry, Ohio University, Athens, OH 45701-2979, USA.
Gehan
G
Heeba
Magdy K A
MK
Hassan
Mohamed
M
Khalifa
Tadeusz
T
Malinski
D000098:Acetophenones / Q000494:pharmacology; D000069059:Atorvastatin; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology
D000098:Acetophenones; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D011758:Pyrroles; C099252:oxidized low density lipoprotein; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D000001:Calcimycin; D000069059:Atorvastatin; D019821:Simvastatin; C056165:acetovanillone; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases