Diesel-induced Vascular Dysfunction: Role of Endothelin

EPA 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.

Expected Results:

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.

Publications and Presentations:

Publications have been submitted on this project: View all 22 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 14 journal articles for this project

Supplemental Keywords:

particulates, pre-existing vascular disease, sudden cardiac death, physiology, hemodynamics, RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Air, HUMAN HEALTH, particulate matter, Toxicology, air toxics, Environmental Chemistry, Health Risk Assessment, Exposure, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, mobile sources, Physical Processes, genetic susceptability, Ecological Risk Assessment, Biology, copollutant exposures, sensitive populations, atmospheric particulate matter, engine exhaust, airway epithelial cells, cardiopulmonary responses, fine particles, inhaled pollutants, acute lung injury, diesel engines, air pollution, susceptible subpopulations, endothelial function, diesel exhaust, automotive exhaust, chronic health effects, lung inflammation, oxidant gas, particulate exposure, cardiopulmonary response, heart rate, ambient particle pollution, Acute health effects, inhaled, highrisk groups, human susceptibility, diesel exhaust particles, cardiotoxicity, cardiopulmonary, diesel exhaust particulate, concentrated particulate matter, air contaminant exposure, air quality, environmental hazard exposures, toxics, airborne urban contaminants, cardiovascular disease, acute exposure

Progress and Final Reports:

  • 2005 Progress Report
  • 2006 Progress Report
  • 2007 Progress Report
  • 2008 Progress Report
  • 2009
  • Final Report