Adverse Balance of Nitric Oxide/Peroxynitrite in the Dysfunctional Endothelium Can be Reversed by Statins

Abstract

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.

Conflicting effects of nitric oxide and oxidative stress in chronic heart failure: potential therapeutic strategies

“…Heeba et al [100] reported that both atorvastatin and simvastatin restored the NO/peroxynitrite balance and decreased malondialdehyde (MDA), as well as wall thickness. In another study examining the effects of statins [101], statins reversed eNOS uncoupling (P \ 0.05) and increased the NO/peroxynitrite balance (P \ 0.05) in controversy to the decrease induced by oxLDL.…”

Attenuation by Statins of Membrane Raft-Redox Signaling in Coronary Arterial Endothelium

“…In addition, non-cholesterol lowering mechanisms by statins have also been attributed to inhibit NADPH oxidase-associated redox signaling (Hattori et al, 2003;Mason et al, 2004;Heeba et al, 2007). For example, statins block HMG-CoA reductase, and the synthesis of isoprenoids and isoprenylation of Rac is essential for Rac translocation to plasma membrane and its activation.…”

Amorphous silica nanoparticles trigger nitric oxide/peroxynitrite imbalance in human endothelial cells: inflammatory and cytotoxic effects

“…[35][36][37] Depleted NO and high ONOO − production by cells resulting in a low ratio (,1.0) of maximal NO to maximal ONOO − concentrations have been used as an accurate indicator of oxidative stress leading to dysfunctional endothelium. 16,18 Therefore, we studied in situ real-time dynamic interaction of the amorphous silica nanoparticles with primary HUVECs by measuring NO and ONOO − concentrations directly using nanosensors placed 5 ± 2 µm from the plasma membrane of a single cell. We demonstrated with time resolution better than 10 microseconds that these nanoparticles rapidly stimulated NO release, followed by ONOO − production after collision with cells ( Figure 2A).…”

“…15 High ONOO − production and depleted NO availability resulting in a low ratio (,1.0) of maximal NO to maximal ONOO − concentrations ([NO]/[ONOO − ]) can be used accurately as an indicator of nitroxidative/oxidative stress and endothelial dysfunction. [16][17][18] It has been suggested that oxidative stress induces upregulation of gene expression by transcription factor activation. 19 When activated, these factors initiate the transcription of several genes involved in inflammation and coagulation.…”