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The Acute Effects of Traffic Pollution on Type II diabetics: Oxidative stress, nitric oxide metabolism and endothelial function

Ashley P. Pettit
B.S., The College of New Jersey - 2006

Thesis Advisors: Howard Kipen, M.D., M.P.H.
Graduate Program in Toxicology

Conference Room A/B

Monday, July 28, 2014
3:00 p.m.


Epidemiological associations between cardiovascular morbidity and mortality and traffic related air pollution(TRAP) are well established.A strong correlation exists between fine particulate pollution and these adverse outcomes,which are associated with decreased vascular endothelial function.The endothelium modulates arterial tone through production of endothelial-derived nitric oxide(EDNO) and interaction with circulating bioavailable sources of NO,such as nitrite.Decreased bioavailable NO has been implicated in the pathogenesis of vascular conditions including diabetes(T2DM) and is linked with increased oxidative stress(OS). Utilized in the clinical assessment of vascular reactivity,reactive hyperemia(RH) results in the acute increase of EDNO;and is reduced in T2DM and following TRAP exposure.
Vascular NO metabolism was examined in diabetic and control subjects following a 2hr highway TRAP exposure.Plasma nitrite(NO2-),a proximal metabolite of EDNO,was increased in controls following RH,and failed to increase following the TRAP exposure;while diabetics showed no change in response to RH,irrespective of exposure conditions.Total NO metabolites(NOx) in the plasma and erythrocytes were not strongly impacted by the presence of T2DM.These concentrations were not changed by TRAP.The ratio of plasma NO2- to NOx following TRAP was not altered in controls,but strongly indicated increased OS in T2DM.
A potential OS source that may result from TRAP exposure is increased inflammatory signaling in circulating monocytes.The effect of a 1hr diesel exhaust(DE) exposure,a model of TRAP,on monocytes was used to identify potential genetic mechanisms of TRAP-related responses.Cells were analyzed by microarray 24 hours after controlled DE or clean air(CA) exposures in healthy subjects.Ingenuity Pathway Analysis identified altered signaling pathways associated with OS,ubiquitination,and coagulation.Real-time PCR was utilized to confirm gene expression changes between CA and DE exposures.
Oxidative metabolism of NO in T2DM,leading to endothelial dysfunction,appears to increase following TRAP exposure.These data suggest that diabetics may be more susceptible to TRAP-related adverse cardiovascular responses,precipitated through immediate effects on vascular NO metabolism.Gene expression alterations within circulating inflammatory cells indicate that decreased bioavailable NO may underlie the observed physiologic and clinical outcomes.These studies establish the possibility of using RH-induced nitrite production as a measure of vascular function in exposure studies and provide a framework for considering the role of inflammation in the cardiovascular response to TRAP.

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