Iron loaded macrophages

Plaques in artery walls are not just cholesterol build up—disadvantaged macrophages play a pivotal role in atherosclerosis.  And you have the power to put an end to their shortcoming.

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Iron loaded macrophages are the cause of atherosclerosis, NOT cholesterol

Hepcidin waving his calculator as he makes iron calculations

Plaques in artery walls are not just cholesterol build up—disadvantaged macrophages play a pivotal role in atherosclerosis. And you have the power to put an end to their shortcoming

If you’re battling with “heart disease” then you KNOW the problem is that your blood vessels are “clogging up with cholesterol”.

The official name for the obstruction is an atheroma.

Cholesterol to blame

We’re told plaques are  made of cholesterol,  but that is a bit of an exaggeration.  The OBSTRUCTION it is a not  just a conglomerate of cholesterol.  Cholesterol, particularly low density lipoprotein, does play a pivotal role, contributing to the fatty deposits.   However, an atheroma is not static, it’s a dynamic site of inflammation where immune cells gather in response to wall injury.

Because cholesterol is there, it’s blamed for the troubles.

There is too MUCH OF IT !

And as the little macrophages do what they can to CLEAN UP THE MESS. They become engorged with it.

Poisoned by cholesterol

Turning from lean mean fighting machines into sedentary unhappy blobs, referred to as foam cells.  Many of these unhappy blobs succumb to the cholesterol load.

They die on site, becoming the necrotic core.

Precipitating a fresh round of clean ups and more deaths.

Containing the damage

Vascular smooth muscle cells do their best to contain the mess, but as the pressure builds, they too succumb, so the overall structure of the blood vessel becomes increasingly unstable.  It doesn’t take too much for the thinner protective barrier to spring a leak or two.

Leaks can quickly morph into spills.

The thinner barrier springing a leak and then blowing

The platelets step into to contain the spill, but blow outs can have catastrophic consequences.

The macrophages are painted as the victims.  But are they ?  After all, mopping up things is part of a macrophages job description.

The macrophage fail

Among the things they are tasked with cleaning up is cell debris, which is always  going to include cell membrane components i.e. cholesterol.   So why do they fail at this crucial job inside blood vessel walls ?

What could be behind this  ?  This was a question a team of researches based in Nanjing, China set about answering.

Disadvantaged macrophages

They suspected the macrophages were arriving at the scene DISADVANTAGED.

Two macrophages lined up to race to a trapped LDL particle. One has a weight tied to its leg

Since moving iron is part of a macrophage’s job description, they wondered if the problem might be they were carrying extra iron i.e. they were iron overloaded.   To explore this idea, they created mice with this SPECIFIC problem i.e. they had iron overloaded macrophages.

NOTE : It’s actually relatively easy to do.  Cells only have one way to export iron, they use a specialized protein known as ferriportin.

Knock outs on steroids

Using sophisticated technology they knocked out (i.e. removed) the ferriportin gene in cells destined to be macrophages.

The iron version of Hotel California.

For these cells, the iron was able to check in any time it liked, but it could  NEVER LEAVE.

This effectively shut down the ability of these animals to recycle iron, setting them up to suffer from  a functional “iron deficiency” anemia.  The iron was still there, it just wasn’t where it’s supposed to be, so the deficiency was functional not absolute. This genetic tweak was combined with another genetic tweak, which put the animals at risk of atherosclerosis.

NOTE : For the record, mice don’t normally develop heart disease, this problem is created by knocking out the ApoE protein, which is  one of the proteins that transports and clears cholesterol and other lipids out of the circulation.   

So what happened in these doubly disadvantaged mice ?

Iron loaded macrophages fail in mice

When the macrophages where unable to clear the iron the development of atherosclerosis was accelerated.  Below, is a photo of what things look like when the animals were 16 weeks old and fed on a high fat diet.

Aortas stained with Oil Red O allowing the atherosclerotic plaques to be visible

Representative images of Oil Red O staining of en face preparations of aortas. The mice suffering from a cacrophage-specific Fpn1 deficiency are shown on right hand side. © Cai et al. 2020

The odd looking stalk like things are aortas that have been stained with Oil Red O.  The red indicates the presence of lipid rich substances, indicating  the presence of abnormal/damaged areas in the blood vessel wall i.e. atherosclerosis.

From this is was clear iron loaded macrophages were failing to move the cholesterol out.

Cholesterol export on hold

When the team took  the macrophages from the mice and let them loose in a lab dish, they noted that the iron loaded macrophages behaved differently.  In the presence of oxidized LDL, the iron loaded macrophages,  turned down the production of the proteins responsible for moving the cholesterol out.

Blot of expression levels of cholesterol transporters and LXR transcription factor

Protein levels of ABCA1, ABCG1, LXR? revealed by Western blot analysis. Macrophage-specific Fpn1 deficiency mice shown on right hand side. © Cai et al. 2020

This can be seen by the much thinner line, next to the ABCA1 staining.  ABCG1 expression was also lower, so was the LXR transcription factor.

The iron is the problem

To confirm that the problem was the extra iron, the team repeated the experiment, but this time they treated the mice with  deferipone, which is an iron chelator i.e.  a substance that grabs hold of iron and takes it out of circulation.

Aorta's stained with Oil Red O when the mice are treated with a iron chelator

Iron chelation therapy prevents severe atherosclerosis in Apoe?/? Fpn1LysM/LysM mice. Representative
images of Oil Red O staining of aortas. © Cai et al. 2020

The aortas looked better.

And the macrophages get with the programme and produce cholesterol transporters.

So what ?

The genetic wonders aren’t relevant

Granted missing  ferriportin pumps and compromised  lipoprotein transporters  make for interesting biology, but have nothing to do with heart attacks in ordinary humans, right ?

Actually the experiment is insightful for two reasons.

Cholesterol off the hook

The first, it let’s cholesterol off the hook,  AGAIN.   This is not a new idea. There is a growing body of evidence suggesting it is time to bury the cholesterol heart disease hypothesis once and for all.   If you want to learn more, visit the cholesterol library page on the better body chemistry blog.

The second insight –  iron is part of the story.

So  is iron to blame ?   

Yes and no. Let’s start with the NO.

Epidemiological evidence hints that high iron is a BIG PROBLEM, we know in people who can’t regulate iron, because they have genetic mutations,  they suffer from all sorts of things, but atherosclerosis is NOT one of them.

List of conditions/diseases associated with hereditary hemochromatosis

The problem was not iron per se, but iron loaded macrophages, which begs the question….can this really happen ?

Actually it can.  In fact, ferriportin “deficiency” in macrophages  is  a relatively  COMMON human reality.

Ferriportin “deficiency” happens

The problem can be genetic, but this is exceedingly rare, it’s more often than not, a body chemistry issue.

  • The  genetic condition that causes someone to have a non-functioning version of ferriportin, EVERYWHERE not just in the macrophages,  it’s called Type 4 hereditary hemochromatosis or ferroportin disease.
  • Bad body chemistry creates a ferroportin “insufficiency”.  The ferriportin pump is there and  it’s capable of doing the job, but it’s not, thanks to hepcidin’s inappropriate actions.

Hepcidin the misguided bully

Hepcidin is the hormone tasked with controlling iron absorption and release. He assesses a variety of factors, to ensure the most “fitting” response for the body’s iron needs.  He factors in

  • iron levels,
  • inflammatory signals,
  • oxygen saturation,
  • erythropoietic demands etc.

When you’re insulin resistant, hepcidin gets the calculations wrong.

Insulin is to blame.

Insulin is the reason you can be iron deficient even when your diet is NOT IRON deficient.  Learn more here.

Iron is a grocery

The reason it happens.  Iron is a grocery a precious, yet dangerous grocery.  Iron spikes, just like sugar spikes are hazardous. So as  a precaution…….

When dinner is served, a puff of hepcidin is released along with insulin.

Beta cell pumping out insulin along with hepcidin

The timely puff, ensures iron transporters are available to move the iron that came with dinner, safely into storage..   

Iron twists and irony

When you’re insulin resistant, insulin levels are high morning, noon and night.   Basically insulin is being pumped out 24/7. Mmm, which means hepcidin is being pumped out 24/7 too.

It is this signaling that keeps iron “trapped” inside macrophages.

Not to the same extent as the genetic obliteration seen in our hapless mice, but enough to speed up the progression of atherosclerosis.  And it’s undesirable consequences.

Heart attacks to heart failure

It creates a situation of  an iron deficiency in the blood stream and key tissues such as the heart, while at the same time, loading up other tissues.

NOTE :  Iron deficiency inside the heart contributes to heart failure – addressing this can go along way to stabilizing the situation.

The fix ? 

These researchers think the solution is to target the iron and I agree.

They’re thinking of doing it pharmacologically i.e. using iron chelators.   And for the record, there is evidence that this can be helpful in humans.

Title of a review journal analyzing the benefits of iron chelators in heart disease

But it’s HARD to get the balance JUST RIGHT, so iron chelators come with a lot of adverse effects and they’re hard to administer. There are other ways to skin the iron cat which are easier and safer…..

Skinning the “iron” cat

Blood donation, is one strategy which helps get the iron moving.  Click here to learn more about this strategy.

My recommendation is to go after the real culprit i.e. rein in insulin.

Insulin and hepcidin posting together to take a selfie

It’s likely to give you the biggest bang for your buck, because high insulin levels (hyperinsulinemia) is behind this and a multitude of other troubles. If you want help getting started, download the Willpower Report, it’s free and begin the journey today to  BETTER BODY CHEMISTRY and better health.

Iron accumulation in macrophages promotes the formation of foam cells and development of atherosclerosis. Cell Biosci (2020) 10:137. Jing Cai, Meng Zhang, Yutong Liu, Huihui Li, Longcheng Shang, Tianze Xu, Zhipeng Chen,Fudi Wang, Tong Qiao and Kuanyu Li

Hereditary Hemochromatosis. American Family Physician (2013) 87 (3) : 183-190. Brian K Crownover, Carlton J Covey. 

Further reading

EPC being exposed to a toxin

Cholesterol clogs up blood vessels because blood vessels fail

A cell lining a blood vessel suffers a catastrophic event AND IS NOT REPLACED, because you’re short of EPCs – cholesterol then fills the leaking pipe, and so it begins.

cholesterol block location

The cholesterol that’s clogging your arteries doesn’t come from the blood

The war on cholesterol, although laudable, is not going to “fix” atherosclerosis, because the blockage starts deep inside the blood vessel, the vasa vasorum is to blame

cholesterol scratching a unwell heart

A low cholesterol number does not guarantee no heart disease

Your cholesterol is within the normal range. CONGRATULATIONS ! Officially you are less likely to die as a result of heart disease. Maybe not.


Want to discover more ways to create BETTER BODY CHEMISTRY ?