Direct Impairment of Vascular Function by Diesel Exhaust Particulate through Reduced Bioavailability of Endothelium-Derived Nitric Oxide Induced by Superoxide Free Radicals

Mark R. Miller, Stephen J. Borthwick, Catherine A. Shaw, Steven G. McLean, Daniel McClure, Nicholas L. Mills, Rodger Duffin, Kenneth Donaldson, Ian L. Megson, Patrick W. F. Hadokel, David E. Newby

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Diesel exhaust particulate (DEP) is a key arbiter of the adverse cardiovascular effects of air pollution.

OBJECTIVES: We assessed the in vitro effects of DEP on vascular function, nitric oxide (NO) availability, and the generation of oxygen-centered free radicals.

METHODS: We assessed the direct vascular effects of DEP (10-100 mu g/mL) in isolated rat aortic rings using myography. We investigated NO scavenging and oxygen-centered free radical generation using an NO electrode and electron paramagnetic resonance (EPR) with the Tempone-H (1-hydroxyl-2,2,6,6-tetramethyl-4-oxo-piperidine) spin trap, respectively.

RESULTS: Acetylcholine-induced relaxation was attenuated by DEP (maximum relaxation reduced from 91 +/- 4% to 49 +/- 6% with 100 mu g/mL DEP; p < 0.001) but was restored by superoxide dismutase (SOD; maximum relaxation, 73 6%; p < 0.001). DEP caused a modest inhibition of relaxation to NO donor drugs, an effect that could be reversed by SOD (p < 0.01). At 10 mu g/mL, DEP did not affect verapamil-induced relaxation (P = 0.73), but at 100 mu g/mL DEP inhibited relaxation (p < 0.001) by a mechanism independent of SOD. NO concentrations generated by 2-(N,N-diethylamino)-diazenotate-2-oxide (DEA/NO; 10 mu M) were reduced by DEP (100 mu g/mL; from 5.2 +/- 0.4 to 3.3 +/- 0.4 mu M; p = 0.002). Free radical generation was increased by DEP (10 mu g/mL; 9-fold increase in EPR spectra;p = 0.004) in a manner that could be attenuated by SOD (p = 0.015).

CONCLUSIONS: DEP caused oxidative stress through the generation of oxygen-centered free radicals that reduced the bioavailability of endothelium-derived NO without prior interaction with the lung or vascular tissue. These findings provide a mechanism for the adverse cardiovascular effects of particulate air pollution.

Original languageEnglish
Pages (from-to)611-616
Number of pages6
JournalEnvironmental Health Perspectives
Volume117
Issue number4
DOIs
Publication statusPublished - Apr 2009

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