Adverse balance of nitric oxide/peroxynitrite in the dysfunctional endothelium can be reversed by statins

• Published in: Journal of cardiovascular pharmacology Vol. 50; no. 4; p. 391
• Main Authors: Heeba, Gehan, Hassan, Magdy K A, Khalifa, Mohamed, Malinski, Tadeusz
• Format: Journal Article
• Language: English
• Published: United States 01.10.2007
• Subjects: Acetophenones - pharmacology; Atorvastatin Calcium; Calcimycin - pharmacology; Cells, Cultured; Dose-Response Relationship, Drug; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiopathology; Enzyme Inhibitors - pharmacology; Heptanoic Acids - pharmacology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Lipoproteins, LDL - pharmacology; NADPH Oxidases - antagonists & inhibitors; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Peroxynitrous Acid - metabolism; Pyrroles - pharmacology; Simvastatin - pharmacology
• ISSN: 0160-2446; 1533-4023
• DOI: 10.1097/FJC.0b013e31811f3fd0

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.