Mechanisms of Diesel-Induced Endothelial N itric Oxide Synthase Dysfunction in Coronary Arterioles.
Cherng TW, Paffett ML, Jackson-Weaver O, Campen MJ, Walker BR, Kanagy NL. Environ Health Perspect. 2010 Sep 22. [Epub ahead of print]
University of New Mexico.
University of New Mexico.
Abstract
Background and objective: Increased air pollutants correlate with increased incidence of cardiovascular disease potentially due to vascular dysfunction. We have reported that acute diesel engine exhaust (DE) exposure enhances vasoconstriction and diminishes acetylcholine (ACh)-induced dilation in coronary arteries in a nitric oxide synthase (NOS)-dependent manner. We hypothesize that acute DE inhalation leads to endothelial dysfunction by uncoupling NOS.
Methods: Rats inhaled fresh DE (300 μg PM/m3) or filtered air for 5 hrs. After off-gassing, intraseptal coronary arteries were isolated and dilation to ACh recorded using videomicroscopy.
Results: Arteries from DE exposed animals dilated less to ACh than arteries from air exposed animals. NOS inhibition did not affect ACh dilation in control arteries but increased dilation in the DE group, suggesting NOS does not normally contribute to ACh-induced dilation in coronary arteries but does contribute to endothelial dysfunction following DE inhalation. COX inhibition did not affect ACh dilation in the DE group, but combined inhibition of NOS and COX diminished dilation in both groups and eliminated inter-group differences suggesting the two pathways interact. Superoxide scavenging increased ACh dilation in DE arteries, eliminating differences between groups. Tetrahydrobiopterin (BH4) supplementation with sepiapterin restored ACh-mediated dilation in the DE group in a NOS dependent manner. Superoxide generation (dihydroethidium staining) was greater in DE arteries and superoxide scavenging, BH4 supplementation or NOS inhibition reduced the signal in DE but not air arteries.
Conclusion: Acute DE exposure appears to uncouple NOS increasing ROS generation and causing endothelial dysfunction, potentially due to depletion of BH4 limiting its bioavailability.
PMID: 20870565 [PubMed - as supplied by publisher]
