Epidemiological studies have linked ambient particulate matter (PM) levels to an increased incidence of adverse cardiovascular events. Yet little is definitively known about the mechanisms accounting for the cardiovascular events associated with PM exposure. The goal of this study was to determine the effects of ultrafine (<0.1 microm) PM exposure on ischemia-reperfusion (I/R) injury. ICR mice were exposed to 100 microg of PM or vehicle by intratracheal instillation. Twenty-four hours later, mice were anesthetized with pentobarbital sodium (60 mg/kg), the left anterior descending coronary artery was ligated for 20 min, flow was restored for 2 h, and the resulting myocardial infarct (MI) size was evaluated. PM exposure doubled the relative size of the MI compared with the vehicle control. No difference was observed in the percentage of the left ventricle at risk for ischemia. PM exposure increased the level of oxidative stress in the myocardium after I/R. The density of neutrophils in the reperfused myocardium was increased by PM exposure, but differences in the number of blood leukocytes, expression of adhesion molecules on circulating neutrophils, and activation state of circulating neutrophils 24 h after PM exposure could not be correlated to the increased I/R injury observed. Additionally, aortas isolated from PM-exposed animals and studied in vitro exhibited a reduced endothelium-dependent relaxation response to acetylcholine. These results indicate that exposure to ultrafine PM increases oxidative stress in the myocardium, alters vascular reactivity, and augments injury after I/R in a murine model.
Virag JA, Dries JL, Easton PR, Friesland AM, DeAntonio JH, Chintalgattu V, Cozzi E, Lehmann BD, Ding JM, Lust RM. Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2.
Deoligomerization of human tumor necrosis factor alpha (TNF), spiked with 125I-labeled form, was studied quantitatively using size-exclusion chromatography and off-line monitoring with a gamma-counter. A detailed investigation of the oligomeric state of TNF was carried out as a function of its own concentration (0.3-7500 nM referred to the subunit, M(r) 17,000) in the absence or in the presence of various amounts (10, 100, 1000 microM) of suramin, an inhibitor of TNF biological activity in vitro, which promotes TNF deoligomerization. The dependence of trimeric form content on total TNF concentration was modeled with a sequential dissociation process (trimer-->dimer-->monomer) assuming an identical dissociation constant for each step, Kd1 = 0.2 nM. This model was used as the simplest for data fitting although, generally, no chromatographic resolution of dimeric species could be obtained. Best fitting of all data could be achieved with a model including a conformational change of TNF trimer into a state more prone to deoligomerization (Kd2 = 400 nM), which was favored by suramin binding. A kinetic study of TNF dissociation by the same method produced values for the deoligomerization rate of trimer: on the average, koff approximately 4 x 10(-5) S-1 (t1/2 approximately 5 h) between 4 and 20 degrees C with little dependence on suramin concentration; at 37 degrees C, a sizable increase is observed in the presence of 1 mM suramin (koff = 2.3 x 10(-4) S-1, t1/2 = 0.8 h). Data of suramin inhibition on TNF receptor binding, as obtained after incubation times much shorter than the above half-life of trimer, indicate that suramin binding to TNF trimer is the early mechanism of receptor binding inhibition.
Epidemiological studies have linked levels of particulate matter (PM) in ambient air to cardiovascular mortality and hospitalizations for myocardial infarction (MI) and stroke. Thrombus formation plays a primary role in potentiating acute cardiovascular events, and this study was undertaken to determine whether pulmonary exposure to PM alters hemostasis. PM was collected from the Chapel Hill, NC airshed and was administered to mice by intratracheal instillation at a dose previously shown to exacerbate myocardial ischemia-reperfusion injury. Twenty-four hours after exposure, an increase occurred in the number of circulating platelets and plasma concentrations of fibrinogen and soluble P-selectin. The concentration of tissue factor pathway inhibitor (TFPI) in plasma was decreased, whereas the plasma concentration of plasminogen activator inhibitor (PAI-1) was increased. Consistent with these observations, bleeding time from a tail-tip transection was shortened. These results provide evidence that PM exposure alters hemostasis in otherwise healthy animals and may thereby promote clot formation and impede clot resolution in susceptible individuals. The results also establish definite hemostatic endpoints that can be used to further investigate the effects of dose and particle characteristics on the toxicity of ambient particles.
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