Cover Picture: Eur. J. Immunol. 7/11

Freigang, Stefan; Ampenberger, Franziska; Spohn, Gunther; Heer, Sebastian; Shamshiev, Abdijapar; Kisielow, Jan; Hersberger, Martin; Yamamoto, Masayuki; Bachmann, Martin F.; Köpf, Manfred

doi:10.1002/eji.201190044

Cited by 3 publications

(4 citation statements)

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“…Surprisingly, we and others have reported three separate studies showing that Nrf2 deficiency in gene-targeted mice leads to decreased atherosclerotic lesions in ApoE null mice (Sussan et al, 2008; Barajas et al, 2011; Freigang et al, 2011), suggesting that its expression may play a proatherogenic role despite its antioxidant actions. Nrf2 −/− ApoE −/− mice developed reduced aortic atherosclerosis as compared to Nrf2 +/− ApoE −/− (Barajas et al, 2011; Freigang et al, 2011) or Nrf2 +/+ ApoE −/− controls (Sussan et al, 2008; Barajas et al, 2011). The type of diet appears to be an important modulating factor as these effects were only seen in males when mice were fed a chow diet (Barajas et al, 2011).…”

Section: Role Of Ho-1 and Other Antioxidant Genes In Atherosclerosismentioning

confidence: 88%

“…Various putative mechanisms, as shown in Figure 4, could mediate Nrf2 proatherogenic effects as recently discussed in an editorial article (Araujo, 2012): (1) Nrf2 expression leads to increased levels of plasma non-HDL cholesterol in Chow-fed ApoE null mice, likely via enhancing liver lipogenesis (Huang et al, 2010; Barajas et al, 2011), (2) Nrf2 promotes foam cell formation, partially due to upregulation of the CD36 scavenger receptor (Ishii et al, 2004; Barajas et al, 2011), (3) Nrf2 enhances increased expression of IL-1α in macrophages which may promote greater monocyte migration to the lesions (Burns and Furie, 1998; Freigang et al, 2011), and (4) Nrf2 may regulate the differentiation of macrophages to subtypes different to the classical M1 and M2, named Mox (Kadl et al, 2010) and possibly Mhem (Boyle et al, 2011, 2012), with functions in atherosclerotic lesion formation still to be determined.…”

Section: Role Of Ho-1 and Other Antioxidant Genes In Atherosclerosismentioning

confidence: 99%

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Heme Oxygenase-1, Oxidation, Inflammation, and Atherosclerosis

Araujo¹,

Zhang²,

Yin³

2012

Front. Pharmacol.

362

263

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Atherosclerosis is an inflammatory process of the vascular wall characterized by the infiltration of lipids and inflammatory cells. Oxidative modifications of infiltrating low-density lipoproteins and induction of oxidative stress play a major role in lipid retention in the vascular wall, uptake by macrophages and generation of foam cells, a hallmark of this disorder. The vasculature has a plethora of protective resources against oxidation and inflammation, many of them regulated by the Nrf2 transcription factor. Heme oxygenase-1 (HO-1) is a Nrf2-regulated gene that plays a critical role in the prevention of vascular inflammation. It is the inducible isoform of HO, responsible for the oxidative cleavage of heme groups leading to the generation of biliverdin, carbon monoxide, and release of ferrous iron. HO-1 has important antioxidant, antiinflammatory, antiapoptotic, antiproliferative, and immunomodulatory effects in vascular cells, most of which play a significant role in the protection against atherogenesis. HO-1 may also be an important feature in macrophage differentiation and polarization to certain subtypes. The biological effects of HO-1 are largely attributable to its enzymatic activity, which can be conceived as a system with three arms of action, corresponding to its three enzymatic byproducts. HO-1 mediated vascular protection may be due to a combination of systemic and vascular local effects. It is usually expressed at low levels but can be highly upregulated in the presence of several proatherogenic stimuli. The HO-1 system is amenable for use in the development of new therapies, some of them currently under experimental and clinical trials. Interestingly, in contrast to the HO-1 antiatherogenic actions, the expression of its transcriptional regulator Nrf2 leads to proatherogenic effects instead. This suggests that a potential intervention on HO-1 or its byproducts may need to take into account any potential alteration in the status of Nrf2 activation. This article reviews the available evidence that supports the antiatherogenic role of HO-1 as well as the potential pathways and mechanisms mediating vascular protection.

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Section: Role Of Ho-1 and Other Antioxidant Genes In Atherosclerosismentioning

confidence: 88%

Section: Role Of Ho-1 and Other Antioxidant Genes In Atherosclerosismentioning

confidence: 99%

Heme Oxygenase-1, Oxidation, Inflammation, and Atherosclerosis

Araujo¹,

Zhang²,

Yin³

2012

Front. Pharmacol.

362

263

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“…429,430 Furthermore, high Nrf2 levels and somatic mutations have been detected in various cancer tissues and Nrf2 plays an important role in the development of chemoresistance. 119,166,431,432 Moreover, Nrf2 has also been found to promote atherosclerosis 224, [433][434][435] and liver damage in autophagy-decient mice. 74,175 Interestingly, RNAi-mediated decrease of Nrf2 expression in lung cancer cells induces the generation of ROS, suppresses tumor growth, and results in increased sensitivity to chemotherapeutic drug-induced cell death in vitro and in vivo.…”

Section: Negative Regulation Of the Nrf2/are Pathwaymentioning

confidence: 99%

Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases

et al. 2014

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Covering: 2000 to 2013. Oxidative stress is the central component of chronic diseases. The nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway is vital in the up-regulation of cytoprotective genes and enzymes in response to oxidative stress and treatment with certain dietary phytochemicals. Herein, we classify bioactive compounds derived from natural products that are Nrf2/ARE pathway activators and recapitulate the molecular mechanisms for inducing Nrf2 to provide favorable effects in experimental models of chronic diseases. Moreover, pharmacological inhibition of Nrf2 signalling has emerged as promising strategy against multi-drug resistance thereby improving the treatment efficacy. We have also enlisted natural product-derived inhibitors of Nrf2/ARE pathway.

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“…Analysis was conducted blinded per individual animal and experimental conditions, and measurements from all sections averaged per mouse. A second assessment of atherosclerosis was conducted in the whole aortas using an en face method 32. Lesion areas were analyzed using a NIS‐Elements software system (Nikon).…”

Section: Methodsmentioning

confidence: 99%

Dietary Docosahexaenoic Acid Reduces Oscillatory Wall Shear Stress, Atherosclerosis, and Hypertension, Most Likely Mediated via an IL‐1–Mediated Mechanism

Alfaidi

Chamberlain

Rothman

et al. 2018

JAHA

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BackgroundHypertension is a complex condition and a common cardiovascular risk factor. Dietary docosahexaenoic acid (DHA) modulates atherosclerosis and hypertension, possibly via an inflammatory mechanism. IL‐1 (interleukin 1) has an established role in atherosclerosis and inflammation, although whether IL‐1 inhibition modulates blood pressure is unclear.Methods and ResultsMale apoE−/− (apolipoprotein E–null) mice were fed either a high fat diet or a high fat diet plus DHA (300 mg/kg per day) for 12 weeks. Blood pressure and cardiac function were assessed, and effects of DHA on wall shear stress and atherosclerosis were determined. DHA supplementation improved left ventricular function, reduced wall shear stress and oscillatory shear at ostia in the descending aorta, and significantly lowered blood pressure compared with controls (119.5±7 versus 159.7±3 mm Hg, P<0.001, n=4 per group). Analysis of atheroma following DHA feeding in mice demonstrated a 4‐fold reduction in lesion burden in distal aortas and in brachiocephalic arteries (P<0.001, n=12 per group). In addition, DHA treatment selectively decreased plaque endothelial IL‐1β (P<0.01).ConclusionsOur findings revealed that raised blood pressure can be reduced by inhibiting IL‐1 indirectly by administration of DHA in the diet through a mechanism that involves a reduction in wall shear stress and local expression of the proinflammatory cytokine IL‐1β.

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Cover Picture: Eur. J. Immunol. 7/11

Cited by 3 publications

References 0 publications

Heme Oxygenase-1, Oxidation, Inflammation, and Atherosclerosis

Heme Oxygenase-1, Oxidation, Inflammation, and Atherosclerosis

Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases

Dietary Docosahexaenoic Acid Reduces Oscillatory Wall Shear Stress, Atherosclerosis, and Hypertension, Most Likely Mediated via an IL‐1–Mediated Mechanism

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