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
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 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.
They suspected the macrophages were arriving at the scene DISADVANTAGED.
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.
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.
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.
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.
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.
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
When dinner is served, a puff of hepcidin is released along with insulin.
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.
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.
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.
Hereditary Hemochromatosis. American Family Physician (2013) 87 (3) : 183-190. Brian K Crownover, Carlton J Covey.
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.
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
Your cholesterol is within the normal range. CONGRATULATIONS ! Officially you are less likely to die as a result of heart disease. Maybe not.