Rationale: Acute and chronic exposures to airborne particulate matter (PM) have been linked in epidemiological studies to a wide spectrum of cardiovascular disorders that are characterized by a dysfunctional endothelium. The pathophysiological mechanisms underlying these associations are unclear. Objective: To examine whether exposure to fine PM with an aerodynamic diameter of <2.5 m (PM 2.5 ) affects the circulating levels of endothelial progenitor cell (EPC) populations, systemic inflammation and coagulation. Methods and Results: Phenotypically distinct EPC populations were quantified by flow cytometry in young (18 to 25 years) adult humans exposed to episodic increases in PM 2.5 along the Wasatch Mountain Front in Utah. In addition, Sca-1 ؉ /Flk-1 ؉ cells were measured in the peripheral blood of mice exposed to concentrated particles from ambient air in Louisville, Ky. In both studies, PM exposure was negatively correlated with circulating EPC levels. In humans, statistically significant associations between PM 2.5 exposure and the plasma levels of platelet-monocyte aggregates, high-density lipoprotein, and nonalbumin protein were also observed. Episodic increases in PM 2.5 did not change plasma levels of C-reactive protein, interleukin-1, interleukin-6, fibrinogen, or serum amyloid A. Conclusions: Episodic exposure to PM 2.5 induces reversible vascular injury, reflected in part by depletion of circulating EPC levels, and increases in platelet activation and the plasma level of high-density lipoprotein. These changes were also accompanied by an increase in nonalbumin protein and may be related to mechanisms by which exposure to particulate air pollution increases the risk of cardiovascular disease and adverse cardiovas- Key Words: endothelial progenitor cell Ⅲ airborne particulate matter Ⅲ pollution Ⅲ endothelial repair A cute and chronic exposure to elevated levels of fine airborne particulate matter (PM) is associated with an increase in the incidence of adverse cardiovascular events, 1,2 atherogenesis, cardiovascular disease (CVD) risk, and cardiovascular mortality. In urban environments, fine PM (PM with aerodynamic diameter of Ͻ2.5 m [PM 2.5 ]) is generated mostly by fossil fuel combustion in automobiles or by industrial processes. Although several mechanisms have been proposed to account for the link between PM exposure and CVD risk, endothelial dysfunction has emerged as a key feature of PM toxicity. Inhalation of concentrated PM 2.5 induces acute conduit artery vasoconstriction in humans and chronic deficits in endothelium-mediated vasodilation in mice. 1,2 The adult endothelium is a differentiated cell layer that provides a nonthrombotic interface between parenchymal cells and peripheral blood. Defects in its function arise because of the upregulated expression of proinflammatory and prothrombotic molecules or from defective, endogenous repair capacity. Evidence from multiple studies suggests that the endothelium is continually repaired by progenitor cells mobilized from specific niches such as th...
Autism spectrum disorder (ASD) is a group of pervasive developmental disorders with core symptoms such as sociability deficit, language impairment, and repetitive/restricted behaviors. Although worldwide prevalence of ASD has been increased continuously, therapeutic agents to ameliorate the core symptoms especially social deficits, are very limited. In this study, we investigated therapeutic potential of donepezil for ASD using valproic acid-induced autistic animal model (VPA animal model). We found that prenatal exposure of valproic acid (VPA) induced dysregulation of cholinergic neuronal development, most notably the up-regulation of acetylcholinesterase (AChE) in the prefrontal cortex of affected rat and mouse offspring. Similarly, differentiating cortical neural progenitor cell in culture treated with VPA showed increased expression of AChE in vitro. Chromatin precipitation experiments revealed that acetylation of histone H3 bound to AChE promoter region was increased by VPA. In addition, other histone deacetyalse inhibitors (HDACIs) such as trichostatin A and sodium butyrate also increased the expression of AChE in differentiating neural progenitor cells suggesting the essential role of HDACIs in the regulation of AChE expression. For behavioral analysis, we injected PBS or donepezil (0.3 mg/kg) intraperitoneally to control and VPA mice once daily from postnatal day 14 all throughout the experiment. Subchronic treatment of donepezil improved sociability and prevented repetitive behavior and hyperactivity of VPA-treated mice offspring. Taken together, these results provide evidence that dysregulation of ACh system represented by the up-regulation of AChE may serve as an effective pharmacological therapeutic target against autistic behaviors in VPA animal model of ASD, which should be subjected for further investigation to verify the clinical relevance.
A basic leucine zipper transcription factor, NF-E2-related factor 2 (Nrf2), plays a critical role in the cellular defense mechanism by mediating a coordinate up-regulation of antioxidant responsive element-driven detoxification and antioxidant genes. Here, we report that targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia due to increased sequestration of damaged erythrocytes. Splenomegaly and spleen toxicity in Nrf2 ؊/؊ mice raised a possibility of hemolytic anemia and splenic extramedullary hematopoiesis in Nrf2 ؊/؊ mice. In support of this, hematology analysis revealed that Nrf2 ؊/؊ mice suffer from anemia with abnormal red cell morphologies (i.e., Howell-Jolly bodies, acantocytes, and schistocytes). In addition, Nrf2 ؊/؊ erythrocytes were more sensitive to H 2O2-induced hemolysis, and erythrocytebound IgG levels were markedly increased in Nrf2 ؊/؊ mice compared with Nrf2 ؉/؉ mice. Because IgG bound to erythrocytes in the presence of oxidative damage in erythrocytes (regardless of Nrf2 genotype), these data support that Nrf2 ؊/؊ erythrocytes have higher levels of damage compared with Nrf2 ؉/؉ cells. Finally, Nrf2 ؊/؊ mice showed increased levels of erythrocyte-bound IgG compared with Nrf2 ؉/؉ mice after H2O2 injection in vivo, suggesting that the decreased glutathione and increased H 2O2 render the Nrf2 ؊/؊ mice more susceptible to toxicity. Taken together, these observations indicate that a chronic increase in oxidative stress due to decreased antioxidant capacity sensitizes erythrocytes and causes hemolytic anemia in Nrf2 ؊/؊ mice, suggesting a pivotal role of Nrf2-antioxidant responsive element pathway in the cellular antioxidant defense system.
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