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Nrf2 also promotes atherosclerosis?

nrf2 atherosclerosis

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#1 Kalliste

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Posted 24 April 2015 - 04:31 AM


I found this article from 2011. I couldn't find a relevant thread so I'm posting it here since it worries me a bit, I have always considered some Nrf2 activation to be prudent.

 

Is this relevant or is this another genetically fucked mice study of little bearing?

(Science20 has a shit webdesign so avoid clicking their link.)

 

 

 

Why haven't antioxidant therapies yielded more positive results?   The answer may be that Nrf2, a protein that plays an important role in some antioxidant therapies, may not be as effective due to additional mechanisms that cause it to promote atherosclerosis - clogging of the arteries.

Nrf2 has been thought to be an important drug-therapy target for diseases such as cancer because it can induce chemopreventive activity by attaching to specific sequences of DNA, leading to the release of numerous antioxidant and anti-inflammatory genes and enzymes that can decrease or inhibit the effects of carcinogens. 

Researchers reasoned that Nrf2, with its potent ability to boost antioxidants, might also be useful in combating the cell and tissue damage, or oxidation, that leads to atherosclerosis.   However, UCLA scientists writing in Arteriosclerosis, Thrombosis and Vascular Biology found that while Nrf2 boosted antioxidant properties in an animal model, it also increased the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver. 

According to researchers, this is the first study to document these additional effects on cholesterol metabolism in tandem with plaque formation in the arteries.

"We were very surprised at the finding," said principal investigator Dr. Jesus Araujo, director of environmental cardiology at the David Geffen School of Medicine at UCLA. "In fact, the atherosclerosis-producing factors were greater than the antioxidant benefits. The development of novel antioxidant therapies is quite important, and this research may help shed light on why treatments affecting this protein may not be as effective as we thought."

For the study, the team was able to isolate and identify Nrf2's actions by looking at what would happen in mice that were specially bred without the protein.

Researchers found that male mice without Nrf2 had decreased levels of antioxidants, as would be expected, but also exhibited a 53 percent reduction in atherosclerotic plaques in the aorta, compared with normal animals. Mice with only half the gene expression for Nrf2 exhibited the same degree of plaque formation as normal animals.

The team then tried to arrive at a better understanding of what was going on by evaluating several factors that could be affected by the Nrf2 protein.

Scientists found that the mice without any Nrf2 had lower levels of total cholesterol in the blood and lower amounts of cholesterol in the liver. The protein deficiency also led to reduced expression of the genes involved in synthesizing and storing fat and regulating glucose in the liver, which are part of the process of manufacturing cholesterol.

According to Araujo, the study findings point to new and important effects of the Nrf2 protein in regulating cholesterol production as well as antioxidant pathways.

"The cholesterol effects may need to be taken into consideration when developing antioxidant therapies using this protein," said Fen Yin, a co-author of the study and a research associate in the division of cardiology at UCLA. "The dosage or level of this gene expression could be important to balance the two effects."

In addition, investigators found that most of the effects of Nrf2 were more highly prevalent in the male mice. More studies will be needed to examine whether these sex differences in the animal model would be similar in humans.

Araujo noted that more research will also assess whether other environmental, metabolic and genetic elements play a role in the impact of Nrf2 on cholesterol and antioxidants.

 



#2 Avatar of Horus

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Posted 24 April 2015 - 08:44 AM

Yes, I've read about it too, but it's hard to give a conclusive answer, compare with for example this study:

Tanshinone IIA suppresses cholesterol accumulation in human macrophages: role of heme oxygenase-1
Liu et al. 2014
http://www.ncbi.nlm....pubmed/24302760
"Abstract
Accumulation of foam cells in the neointima represents a key event in atherosclerosis. We previously demonstrated that Tanshinone IIA (Tan), a lipophilic bioactive compound extracted from Salvia miltiorrhiza Bunge, inhibits experimental atherogenesis, yet the detailed mechanisms are not fully understood. In this study, we sought to explore the potential effects of Tan on lipid accumulation in macrophage foam cells and the underlying molecular mechanisms. Our data indicate that Tan treatment reduced the content of macrophages, cholesterol accumulation, and the development of atherosclerotic plaque in apolipoprotein E-deficient mice. In human macrophages, Tan ameliorated oxidized low density lipoporotein (oxLDL)-elicited foam cell formation by inhibiting oxLDL uptake and promoting cholesterol efflux. Mechanistically, Tan markedly reduced the expression of scavenger receptor class A and increased the expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 in lipid-laden macrophages via activation of the extracellular signal-regulated kinase (ERK)/nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. Tan treatment induced the phosphorylation and nuclear translocation of Nrf2 and subsequently increased the expression of HO-1, and these effects were abolished by the specific ERK inhibitors, PD98059 and U0126. Moreover, HO-1 small interfering RNA or zinc protoporphyrin (a HO-1 inhibitor) abrogated Tan-mediated suppression of lipid accumulation in macrophages. Our current findings demonstrate that a novel HO-1-dependent mechanism is involved in the regulation of cholesterol balance by Tan."

The authors mention and discuss the study (Barajas et al.) on which your quote is based:
http://www.jlr.org/c...t/55/2/201.long
"The previous studies by Sussan et al. (51) and Barajas et al. (52) have consistently shown that Nrf2 expression promotes atherosclerotic lesion formation in ApoE-/- mice, which is associated with increased expression of scavenger receptor CD36. It is therefore paradoxical that Tan activates Nrf2 and inhibits atherogenesis. Nevertheless, our results show that Tan activates Nrf2 without enhancing the expression of CD36. Thus, it seems that Tan can achieve anti-oxidant and anti-inflammatory protection mediated by Nrf2 activation and avoid enhanced oxLDL uptake mediated by increased expression of CD36. Another potential explanation is that Tan-mediated HO-1 induction may not be entirely Nrf2-dependent. In this way, increased HO-1 expression by other pathways could have overshadowed the proatherogenic effects that could potentially be derived from Nrf2 activation.

One study limitation is that the present studies were mainly performed in human macrophages in vitro. Thus, the interpretation of the present data should be cautious, and further studies using in vivo approaches are necessary to verify the present results in future experiments. Systemic HO-1-/-ApoE-/- mice or macrophage-specific HO-1-/- mice are feasible approaches to demonstrate the direct role of HO-1 in the Tan-mediated suppressive effects on foam cells in vivo. Importantly, Tan has been widely used in Asian countries to prevent and treat CVDs. Therefore, further experiments in patients with atherosclerosis are required to confirm the anti-atherogenic effect of Tan.

In summary, our study demonstrates that Tan decreases SR-A-mediated oxLDL uptake via inhibition of AP-1 and increases ABCA1/G1-mediated cholesterol efflux via the ERK/Nrf2/HO-1 pathway, ultimately resulting in reduced cholesterol accumulation in foam cells and atherosclerotic plaques (Fig. 8). These findings indicate a critical role of HO-1 in Tan-mediated suppressive effects on foam cell formation. Our present study sheds a novel light on the understanding of the molecular mechanisms of Tan and the clinical application of Tan to treat patients with atherosclerotic CVDs."
 
Figure 8 for an overview:
Liu_et_al_2014_F8_large600.jpg
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