Abstract-Air pollution is associated with significant adverse health effects, including increased cardiovascular morbidity and mortality. Exposure to particulate matter with an aerodynamic diameter of Ͻ2.5 m (PM 2.5 ) increases ischemic cardiovascular events and promotes atherosclerosis. Moreover, there is increasing evidence that the smallest pollutant particles pose the greatest danger because of their high content of organic chemicals and prooxidative potential. To test this hypothesis, we compared the proatherogenic effects of ambient particles of Ͻ0.18 m (ultrafine particles) with particles of Ͻ2.5 m in genetically susceptible (apolipoprotein E-deficient) mice. These animals were exposed to concentrated ultrafine particles, concentrated particles of Ͻ2.5 m, or filtered air in a mobile animal facility close to a Los Angeles freeway. Ultrafine particle-exposed mice exhibited significantly larger early atherosclerotic lesions than mice exposed to PM 2.5 or filtered air. Exposure to ultrafine particles also resulted in an inhibition of the antiinflammatory capacity of plasma high-density lipoprotein and greater systemic oxidative stress as evidenced by a significant increase in hepatic malondialdehyde levels and upregulation of Nrf2-regulated antioxidant genes. We conclude that ultrafine particles concentrate the proatherogenic effects of ambient PM and may constitute a significant cardiovascular risk factor. (Circ Res. 2008;102:589-596.)
Objective-To test the hypothesis that NF-E2-related factor 2 (Nrf2) expression plays an antiatherogenic role by its vascular antioxidant and anti-inflammatory properties. Methods and Results-Nrf2 is an important transcription factor that regulates the expression of phase 2 detoxifying enzymes and antioxidant genes. Its expression in vascular cells appears to be an important factor in the protection against vascular oxidative stress and inflammation. We developed Nrf2 heterozygous (HET) and homozygous knockout (KO) mice on an apolipoprotein (apo) E-null background by sequential breeding, resulting in Nrf2 Ϫ/Ϫ , apoE Ϫ/Ϫ (KO), Nrf2, apoE Ϫ/Ϫ (HET) and Nrf2, and apoE Ϫ/Ϫ wild-type littermates. KO mice exhibited decreased levels of antioxidant genes with evidence of increased reactive oxygen species generation compared with wild-type controls. Surprisingly, KO males exhibited 47% and 53% reductions in the degree of aortic atherosclerosis compared with HET or wild-type littermates, respectively. Decreased atherosclerosis in KO mice correlated with lower plasma total cholesterol in a sex-dependent manner. KO mice also had a decreased hepatic cholesterol content and a lower expression of lipogenic genes, suggesting that hepatic lipogenesis could be reduced. In addition, KO mice exhibited atherosclerotic plaques characterized by a lesser macrophage component and decreased foam cell formation in an in vitro lipid-loading assay. This was associated with a lower rate of cholesterol influx, mediated in part by decreased expression of the scavenger receptor CD36. A therosclerosis is a chronic inflammatory disease with both genetic and environmental components, 1,2 characterized by the deposition of lipids in the artery wall and the infiltration of inflammatory cells, such as monocytes and lymphocytes. Vascular oxidative stress is thought to be an important element in its pathogenesis. Indeed, oxidative modifications of low-density lipoprotein (LDL) in the subendothelial space with subsequent generation of foam cells is 1 of the earliest events in atherogenesis. 3 In addition, endothelial cells, macrophages, and smooth muscle cells are all sources of reactive oxygen species (ROS). 4 -6 Therefore, the interplay between pro-oxidant and antioxidant factors is likely to be of key importance, 7 although this notion has been questioned on the basis that oxidative modifications could be consequential, rather than causal, to atherosclerotic lesion formation. 8 Vascular cells express an extensive repertoire of antioxidant genes and phase 2 detoxifying enzymes regulated by a transcription factor, NF-E2-related factor 2 (Nrf2). Nrf2 is a member of the Cap and Collar subfamily of basic leucine zipper transcription factors that act through the formation of a heterodimer with 1 of the small Maf proteins 9 and bind to a cis-acting enhancer sequence, known as the antioxidant response element, 10 -13 in the 5Ј-flanking regions of its target genes. 12 Although the regulation of Nrf2 activity is not completely understood, it appears that ...
Abstract-Heme oxygenase (HO-1) is the rate-limiting enzyme in the catabolism of heme, which leads to the generation of biliverdin, iron, and carbon monoxide. It has been shown to have important antioxidant and antiinflammatory properties that result in a vascular antiatherogenic effect. To determine whether HO-1 expression in macrophages constitutes a significant component of the protective role in atherosclerosis, we evaluated the effect of decreased or absent HO-1 expression in peritoneal macrophages on oxidative stress and inflammation in vitro, and the effect of complete deficiency of HO-1 expression in macrophages in atherosclerotic lesion formation in vivo. We found that compared with HO-1 ϩ/ϩ controls, peritoneal macrophages from HO-1 Ϫ/Ϫ and HO-1 ϩ/Ϫ mice exhibited (1) increased reactive oxygen species (ROS) generation, (2) increased proinflammatory cytokines such as monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6), and (3) increased foam cell formation when treated with oxLDL, attributable in part to increased expression of scavenger receptor A (SR-A). Bone marrow transplantation experiments performed in lethally irradiated LDL-R null female mice, reconstituted with bone marrow from HO-1 Ϫ/Ϫ versus HO-1 ϩ/ϩ mice, revealed that HO-1 Ϫ/Ϫ reconstituted animals exhibited atherosclerotic lesions with a greater macrophage content as evaluated by immunohistochemistry and planimetric assessment. We conclude that HO-1 expression in macrophages constitutes an important component of the antiatherogenic effect by increasing antioxidant protection and decreasing the inflammatory component of atherosclerotic lesions.
Air pollutant effects on endothelial cells Gene expression analysis of human microvascular endothelial cells exposed to diesel exhaust particles and oxidized phospholipids revealed several upregulated gene modules, including genes involved in vascular inflammatory processes such as atherosclerosis.
SFN and NAC upregulate T(H)1 immunity in aging through a restoration of redox equilibrium.
Particulate matter (PM) is an important risk factor for asthma. Generation of oxidative stress by PM is a major mechanism of its health effects. Transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) mediates antioxidant and phase II enzymes and is essential in protecting against oxidative stress and lung inflammation. We have previously shown that ambient ultrafine particles (UFP) could exert a potent adjuvant effect on allergic sensitization to ovalbumin (OVA) in mice. We hypothesized that Nrf2 deficiency in dendritic cells (DC) could enhance the adjuvant potential of UFP on allergic sensitization. We show that the adjuvant effect of intranasally instilled UFP is significantly enhanced in Nrf2 knockout (Nrf2-/-) mice compared with their wild-type (Nrf2+/+) counterparts. Under resting conditions, Nrf2-/- DC displayed an intrinsic predilection to a T helper 2-favoring cytokine profile characterized by a low level of IL-12p70 and a high level of IL-6 as compared to Nrf2+/+ DC. Adoptive transfer of OVA/UFP-treated Nrf2-/- DC provoked a more severe allergic inflammation in the lung than Nrf2+/+ DC in the same treatment group. We conclude that Nrf2 deficiency in DC may promote a constitutive immune-polarizing cytokine milieu, which we propose may have contributed to the augmented adjuvant effect of UFP on allergic sensitization.
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