Diesel-induced Vascular Dysfunction: Role of EndothelinEPA Grant Number: R831860
Title: Diesel-induced Vascular Dysfunction: Role of Endothelin
Investigators: Kanagy, Nancy L. , Campen, Matthew J. , Walker, Benjimen R.
Institution: University of New Mexico , Lovelace Respiratory Research Institute
EPA Project Officer: Chung, Serena
Project Period: October 1, 2004 through September 30, 2008 (Extended to September 30, 2010)
Project Amount: $1,500,000
RFA: The Role of Air Pollutants in Cardiovascular Disease (2003) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Air , Health Effects , Particulate Matter
There is a clear association between air pollution exposure and cardiovascular mortality. However, the mechanisms linking air pollution to cardiovascular events are poorly understood. Inhalation of particulate matter (PM) air pollution has been shown to increase the release of vasoactive cytokines such as endothelin while individuals with vascular disease have augmented vasoconstrictor responses to this peptide. Therefore, diesel exhaust-released endothelin could contribute to air pollution-induced cardiovascular events in sensitized individuals. We propose to use a novel model of endothelin dependent hypertension and endothelial dysfunction, paired with state-of-the-art methods for generating whole diesel exhaust, to investigate cardiovascular effects of PM. Our recent studies demonstrate that simulating sleep apnea by exposing rats to 90 second episodes of intermittent hypoxia/hypercapnia (IH) for 8 hours a day causes hypertension that is reversed by endothelin antagonists and associated with increased endothelin synthesis, augmented endothelin vasoconstriction and both right and left ventricular hypertrophy. Our preliminary studies show that whole diesel exhaust stimulates ET-1 synthesis and increases oxidative stress. Our central hypothesis is that inhalation of whole DE augments ROS stimulation of ET vasoconstriction in rats with IH-induced hypertension.
Our specific aims are: 1) To determine the effect of 6 hours of DE inhalation on plasma and tissue ET levels in Sham and IH hypertensive rats. These studies will test the hypothesis that DE stimulated ET synthesis is augmented in IH rats. We will examine tissue and plasma levels of ET-1, -2, and -3 and vascular expression of ETA- and ETB-receptors. 2) To determine the role of ROS in ET synthesis in IH and Sham rats at baseline and following DE inhalation. These studies will determine if elevated basal ROS levels sensitize IH rats to DE stimulation of ET vasoconstriction and if DE stimulation of ROS is necessary for increased ET synthesis. Tissue and plasma thiobarbiturate reactive substances (TBARS) will be measured at baseline and following DE inhalation as a measure of ROS generation. The effect of systemic antioxidants (Tempol 30 mg/kg/day) on ET synthesis will determine the contribution of ROS to DE stimulation of ET synthesis.
These studies are expected to determine mechanisms underlying the increased vascular pathology in response to DE inhalation in patients with pre-existing vascular disease. The widespread incidence of sleep apnea makes this relevant to a large segment of the population. This collaboration between NLK and BRW at the University of New Mexico and MJC at LRRI uniquely brings together expertise in environmental exposure toxicology and cardiovascular/hypertension physiology as part of the research consortium in the New Mexico NIEHS Center.