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Superfund Research Program

Environmentally Persistent Free Radicals Increase Cardiac Vulnerability to Ischemia

Project Leader: Kurt J. Varner
Co-Investigator: Huijing Xia (LSU Health Sciences Center - New Orleans)
Grant Number: P42ES013648
Funding Period: 2011-2018
View this project in the NIH Research Portfolio Online Reporting Tools (RePORT)

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Project Summary (2011-2018)

Epidemiological studies consistently show a positive relationship between airborne particulate matter (PM) and increased morbidity and mortality from cardiovascular disease. The mechanisms underlying PM-associated cardiovascular toxicity are largely unknown. Dr. Kurt Varner's research group has discovered aromatic chlorinated hydrocarbons combine with metal-containing PM to form surface stabilized, environmentally persistent free radicals (EPFRs). They have shown that EPFRs:

  1. Are capable of redox cycling and continuously forming reactive oxygen species.
  2. Produce inflammation and oxidative stress (OS) in the lung.
  3. Increase the expression of proinflammatory genes in the heart.
  4. Produce cardiac inflammation.
  5. Decrease left ventricular function in vivo.
  6. Increase OS and the magnitude of cardiac ischemia/reperfusion injury (I/R).

These data suggest EPFR-mediated OS and inflammation underlies the observed functional deficits and increased vulnerability to I/R injury. Cellular homeostasis in response to OS and inflammation is maintained by the balanced activation of tier 2 antioxidant genes via the transcription factor, Nrf2, and the proinflammatory NFκB pathway. Dr. Varner hypothesizes that: EPFR-induced oxidative stress and inflammation enhance cardiac injury and dysfunction by "tipping the balance" between the antioxidant Nrf2 and the proinflammatory NFκB pathway to favor NFκB. To test this hypothesis, he proposes 3 specific aims:

  1. Determine the dose-response relationship between EPFRs and cardiac function in vivo and characterize OS and inflammatory responses in the heart and lungs.
  2. Explore the ability of EPFRs to increase infarct size and enhance the deficits in left ventricular function after I/R injury in vivo.
  3. Explore the effect of EPFR exposure on the activity of the Nrf2 antioxidant and NFκB inflammatory pathways.

This research relies on the interdisciplinary strengths of the LSU-SRP. Lung tissue from this study is being analyzed for OS and inflammation by Dr. Stephania Cormier. Dr. Wayne Backes is examining P450 expression and function with respect to OS in the cardiac tissue samples. Dr. Varner is also drawing heavily on the expertise and analysis performed by the Oxidative Stress Core, while all of the samples tested will be generated by the Materials Core.

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