$54,000
$15,970

Support for Oxidized Cholesterol as a Primary Cause of Atherosclerosis

In the paper I'll point out today, the authors provide evidence in support of the concept that it is specifically oxidized cholesterol that is the primary cause of atherosclerosis rather than the condition resulting from too much cholesterol in general. In atherosclerosis, fatty deposits form in blood vessel walls, weakening them and narrowing the vessels. This ultimately leads to fatal structural failure as stressed blood vessels rupture or are blocked. Atherosclerosis is arguably a condition that arises because the macrophages responsible for removing cholesterol from blood vessel walls become overwhelmed, inflammatory, and incapable of keeping up the work of maintenance and repair. They become foam cells and die, adding their contents and their remnants to grow an atherosclerotic plaque, and attracting more of their fellows to the same location to repeat the cycle.

Here it is argued that this foam cell fate is largely the consequence of oxidized cholesterol. The macrophages are reacting to oxidized cholesterol in ways that sabotage their efforts to remove local deposits of cholesterol. The approach to this condition adopted by the SENS rejuvenation research programs is to find ways to break down the oxidized cholesterol that our cells struggle to deal with. Removing it from the picture should enable cells to continue as they were, and remove the fatty deposits. Researchers associated with the SENS Research Foundation have searched for bacteria capable of consuming these damaged forms of cholesterol, in order to adapt their enzymes into therapeutic molecules. This work has to date largely focused on 7-ketocholesterol, with some early success, but a broader and more heavily funded research program is very much called for.

Modified LDL particles activate inflammatory pathways in monocyte-derived macrophages

One of the main characteristics of atherosclerosis is the accumulation of lipids in the intimal layer of the arterial wall. In atherosclerotic plaques, phagocytic cells, such as macrophages, engulf atherogenic low-density lipoprotein (LDL) particles, but are unable to process them, and thus become foam cells, having cytoplasm packed with lipid droplets. Foam cells are characterized by several typical features: they have decreased ability to migrate, while displaying enhanced production of pro-inflammatory cytokines. Therefore foam cells participate in maintaining chronic inflammation in the lesion.

Previous studies have shown several clusters of genes up- or down-regulated in macrophages in response to oxidized LDL, which is known to be atherogenic. Regarding the inflammatory response, modified LDL appeared to trigger up-regulation of genes with anti-inflammatory activities. We performed a transcriptome analysis of macrophages treated with atherogenic LDL that causes intracellular cholesterol accumulation. We used the strategy of upstream analysis for causal interpretation of the expression changes.

In this study, we discovered 27 transcription factors that were potentially responsible for the changes in gene expression induced by modified atherogenic LDL. These transcription factors were used for identifying the master-regulators (genes and proteins) responsible for regulation of large cascades of differentially expressed genes. In general, the genes that were up-regulated in response to lipid accumulation in macrophages induced by atherogenic LDL were mostly involved in inflammation and immune response, and not in cholesterol metabolism. Our results suggest a possibility that it is not cholesterol accumulation that causes an innate immunity response, but rather the immune response is a consequence of a cellular reaction to modified LDL. These results highlight the importance of the inflammatory component in the pathogenesis of atherosclerosis.

Modified LDL Particles Activate Inflammatory Pathways in Monocyte-derived Macrophages: Transcriptome Analysis

A hallmark of atherosclerosis is its complex pathogenesis, which is dependent on altered cholesterol metabolism and inflammation. Both arms of pathogenesis involve myeloid cells. Monocytes migrating into the arterial walls interact with modified low-density lipoprotein (LDL) particles, accumulate cholesterol and convert into foam cells, which promote plaque formation and also contribute to inflammation by producing proinflammatory cytokines. A number of studies characterized transcriptomics of macrophages following interaction with modified LDL, and revealed alteration of the expression of genes responsible for inflammatory response and cholesterol metabolism. However, it is still unclear how these two processes are related to each other to contribute to atherosclerotic lesion formation.

We attempted to identify the main master regulator genes in macrophages treated with atherogenic modified LDL using a bioinformatics approach. We found that most of the identified genes were involved in inflammation, and none of them was implicated in cholesterol metabolism. Among the key identified genes were interleukin (IL)-7, IL-7 receptor, IL-15, and CXCL8. Our results indicate that activation of the inflammatory pathway is the primary response of the immune cells to modified LDL, while the lipid metabolism genes may be a secondary response triggered by inflammatory signalling.

Comments

An alternative approach to using small molecule to dissolve the plaques would be to genetically engineer macrophages that are resistant to the oxydized LDL and inject them in the bloodstream. Although that might require damping down the inflammatory response and, as result, infection fighting effectiveness.

Posted by: cuberat at November 1st, 2018 5:28 PM

Or you could just take some nattokinase capsules or eat natto.

Nattokinase reversed plaque and increased HDL in humans:
"The reduction in the NK group was significantly profound (P<0.01, 36.6% reduction in plaque size in NK group versus 11.5% change in ST group). "

https://www.ncbi.nlm.nih.gov/pubmed/28763875

Posted by: Lee at November 1st, 2018 6:47 PM

@Lee: That is pretty interesting. The result size is large enough to be suspicious of, and want to see replication. The compound itself has a lot of smoke without fire in its history (i.e. why no earlier studies, given the length of time it has been under study?). There is a more recent review:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043915/

Posted by: Reason at November 1st, 2018 7:10 PM

This is amazingly good news. I'll bet this study has the statins big pharma crowd in a tizzy.

Posted by: Tom Schaefer at November 2nd, 2018 9:18 AM

As far as I'm concerned this has been an open secret for some time. But it's taking a while for the penny to drop.

Posted by: Mark at November 2nd, 2018 11:49 AM

@Lee at November
Just a month ago I had the impression that the scientific consensus is that the cholesterol build up never gets reduced and only this week a see at least two posts suggesting that it is quite reversible without extreme diets or operations... Now I cannot help but ask why on earth people still die from repeated heart attacks on massive scale?

Posted by: cuberat at November 2nd, 2018 4:29 PM

@Reason
My layman's guess is that nattokinase is working in at least two ways: Modifying the gut microbiome and also dissolving some components of the plaque. I think serrapeptase would work too. I have experimented with serrapeptase and noticed a few tiny age spot freckles on my hands disappear so maybe it is an AGE breaker. I currently eat a home-made chickpea natto daily. I am 57 and had a heart attack and stent at 54 with probably <10% bodyfat at a BMI of about 25 and being fit, strong and highly active.

Olmesartan has shown plaque reversal too. You might want to look up Trevor Marshall regarding your thymus rejuvenation venture. He spent the last 15 years investigating Olmesartan's off-label use for immune stimulation.

Thank you for your informative blog. Thanks to you we might both catch the LEV boat.

Posted by: Lee at November 2nd, 2018 5:05 PM

" it is specifically oxidized cholesterol that is the primary cause of atherosclerosis rather than the condition resulting from too much cholesterol in general."

Hmm, so excuse me for asking, but does that mean if you just avoid cholesteral intake in general (even if just oxidised chol is bad), then you that may help you avoid atherosclerosis to some extent? Does that assumption make sense or is it total nonsense? My reason for asking is that my goal is to turn this info into practical advice for myself , I want to somehow try to incorporate the latest research into my life if at all possible. I have no understanding about how to lower oxidiaed chol for now, so my best guess is lowering general cholesterol intake. Feel free to enlighten me, I'm here to learn and make sense of all information that is presented on this blog.

Posted by: Purely Biological at November 2nd, 2018 9:59 PM

@Purely Biological
>does that mean if you just avoid cholesteral intake in general (even if just oxidised chol is bad), then you that may help you avoid atherosclerosis to some extent

Yes, to some extent. In fact, that's the whole point of low fat foods and lifestyle. However, the body can easily convert carbs to cholesterol since it is extension for many processes. But still low cholesterol diets help, especially if combined with statins.

Posted by: Cuberat at November 3rd, 2018 9:28 AM

Research showing oxidized LDL as a cause of atherosclerosis is reviewed towards the end of this video. I'm interested in the oxLDL assay mentioned by the speaker:

The Cholesterol Conundrum Part 2: Putting LDL Particle Count into Context
https://youtube.com/watch?v=hFkrGIYIM74

Posted by: NY2LA at November 4th, 2018 2:27 AM

Triglycerides are the real killer - better to avoid sugar than cholesterol in the diet.

Posted by: Mark at November 5th, 2018 3:15 AM

This suggests that any therapy that reduces oxidation should help. I.e., this should be a boost to MitoQ and other mitochondrially-targeted anti-oxidants and to the oxidation-resistant deuterated lipids (D-PUFAs) of Retrotope.

Posted by: Karl Pfleger at November 7th, 2018 5:54 PM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.