Epidemiological studies consistently show a positive relationship between airborne matter (PM) and increased morbidity and mortality from cardiovascular disease. The mechanisms underlying PM-associated cardiovascular toxicity are largely unknown. We have discovered aromatic chlorinated hydrocarbons combine with metal-containing PM to form surface stabilized, environmentally persistent free radicals (EPFRs). We 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, and 6) increase OS and the magnitude of cardiac ischemia/reperfusion injury (l/R). These data suggest EPFR mediated OS and inflammation underlies the observed functional deficits and increased vulnerability to l/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 NfKB pathway. We hypothesize that: EPFR-induced oxidative stress and inflammation enhance cardiac injury and dysfunction by """"""""tipping the balance"""""""" between the antioxidant Nrf2 and the proinflammatory NFKB pathway to favor NFKB. TO test this hypothesis, we propose 3 specific aims.
Aim 1 will determine the dose-response relationship between EPFRs and cardiac function in vivo and will characterize OS and inflammatory responses in the heart and lungs.
Aim 2 will explore the ability of EPFRs to increase infarct size and enhance the deficits in left ventricular function after l/R injury in vivo.
Aim 3 will explore the effect of EPFRs exposure on the activity of the Nrf2 antioxidant and NFkB inflammatory pathways. Project 4 relies on the interdisciplinary strengths of the LSU-SRP. Lung tissue from our studies will be analyzed for OS and inflammation in Project 2. Project 5 will examine P450 expression and function with respect to OS in our cardiac tissue. We will also draw 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.
Our observation that EPFRs decrease cardiac function and increase cardiac vulnerability to ischemic injury poses a substantial and virtually unstudied risk factor for individuals having or at risk of developing ischemic heart disease. This increased vulnerability, may explain the causal relationship between exposure to airborne particulates and increased cardiovascular morbidity and mortality.
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