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[Kalliste]

The obvious question is, are there any supplements that target KLF4? 

 

 

 

Fundamental beliefs about atherosclerosis overturned Complications of artery-hardening condition are number one killer worldwide Date: July 6, 2015 Source: University of Virginia Health System Summary: Doctors' efforts to battle the dangerous atherosclerotic plaques that build up in our arteries and cause heart attacks and strokes are built on several false beliefs about the fundamental composition and formation of the plaques, new research shows. These new discoveries will force researchers to reassess their approaches to developing treatments and discard some of their basic assumptions about atherosclerosis, commonly known as hardening of the arteries. Share:

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Anatomical model of human heart. Until now, doctors have believed that smooth muscle cells -- the cells that help blood vessels contract and dilate -- were the good guys in the body's battle against atherosclerotic plaque. (Stock image)

Credit: © snike / Fotolia

 

Anatomical model of human heart. Until now, doctors have believed that smooth muscle cells -- the cells that help blood vessels contract and dilate -- were the good guys in the body's battle against atherosclerotic plaque. (Stock image)

Credit: © snike / Fotolia

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Doctors' efforts to battle the dangerous atherosclerotic plaques that build up in our arteries and cause heart attacks and strokes are built on several false beliefs about the fundamental composition and formation of the plaques, new research from the University of Virginia School of Medicine shows. These new discoveries will force researchers to reassess their approaches to developing treatments and discard some of their basic assumptions about atherosclerosis, commonly known as hardening of the arteries.

"The leading cause of death worldwide is complications of atherosclerosis, and the most common end-stage disease is when an atherosclerotic plaque ruptures. If this occurs in one of your large coronary arteries, it's a catastrophic event," said Gary K. Owens, PhD, of UVA's Robert M. Berne Cardiovascular Research Center. "Once a plaque ruptures, it can induce formation of a large clot that can block blood flow to the downstream regions. This is what causes most heart attacks. The clot can also dislodge and cause a stroke if it lodges in a blood vessel in the brain. As such, understanding what controls the stability of plaques is extremely important. "

Until now, doctors have believed that smooth muscle cells -- the cells that help blood vessels contract and dilate -- were the good guys in the body's battle against atherosclerotic plaque. They were thought to migrate from their normal location in the blood vessel wall into the developing atherosclerotic plaque, where they would attempt to wall off the accumulating fats, dying cells and other nasty components of the plaque. The dogma has been that the more smooth muscle cells in that wall -- particularly in the innermost layer referred to as the "fibrous cap" -- the more stable the plaque is and the less danger it poses.

UVA's research reveals those notions are woefully incomplete at best. Scientists have grossly misjudged the number of smooth muscle cells inside the plaques, the work shows, suggesting the cells are not just involved in forming a barrier so much as contributing to the plaque itself. "We suspected there was a small number of smooth muscle cells we were failing to identify using the typical immunostaining detection methods. It wasn't a small number. It was 82 percent," Owens said. "Eighty-two percent of the smooth muscle cells within advanced atherosclerotic lesions cannot be identified using the typical methodology since the lesion cells down-regulate smooth muscle cell markers. As such, we have grossly underestimated how many smooth muscle cells are in the lesion."

Suddenly, the role of smooth muscle cells is much more complex, much less black-and-white. Are they good or bad? Should treatments try to encourage more? It's no longer that simple, and the problem is made all the more complicated by the fact that some smooth muscle cells were being misidentified as immune cells called macrophages, while some macrophage-derived cells were masquerading as smooth muscle cells. It's very confusing, even for scientists, and it has led to what Owens called "complete ambiguity as to which cell is which within the lesion." (The research also shows other subsets of smooth muscle cells were transitioning to cells resembling stem cells and myofibroblasts.)

Researcher Laura S. Shankman, a PhD student in the Owens lab, was able to overcome the limitations of the traditional methodology for detecting smooth muscle cells in the plaque. Her approach was to genetically tag smooth muscle cells early in their development, so she could follow them and their descendants even if they changed their stripes. "This allowed us to mark smooth muscle cells when we were confident that they were actually smooth muscle cells," she said. "Then we let the atherosclerosis develop and progress [in mice] in order to see where those cells were later in disease."

Further, Shankman identified a key gene, Klf4, that appears to regulate these transitions of smooth muscle cells. Remarkably, when she genetically knocked out Klf4 selectively in smooth muscle cells, the atherosclerotic plaques shrank dramatically and exhibited features indicating they were more stable -- the ideal therapeutic goal for treating the disease in people. Of major interest, loss of Klf4 in smooth muscle cells did not reduce the number of these cells in lesions but resulted in them undergoing transitions in their functional properties that appear to be beneficial in disease pathogenesis. That is, it switched them from being "bad" guys to "good" guys.

Taken together, Shankman's findings raise many critical questions about previous studies built on techniques that failed to assess the composition of the lesions accurately. Moreover, her studies are the first to indicate that therapies targeted at controlling the properties of smooth muscle cells within lesions may be highly effective in treating a disease that is the leading cause of death worldwide.

The discoveries have been outlined in a paper published online by the journal Nature Medicine.

 

Story Source:

The above post is reprinted from materials provided by University of Virginia Health System. Note: Materials may be edited for content and length.

Journal Reference:

1. Laura S Shankman, Delphine Gomez, Olga A Cherepanova, Morgan Salmon, Gabriel F Alencar, Ryan M Haskins, Pamela Swiatlowska, Alexandra A C Newman, Elizabeth S Greene, Adam C Straub, Brant Isakson, Gwendalyn J Randolph, Gary K Owens. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nature Medicine, 2015; 21 (6): 628 DOI: 10.1038/nm.3866

 

Edited by Cosmicalstorm, 07 July 2015 - 08:00 AM.

[Daniel Cooper]

This looks very interesting. 

 

I wonder if something that would down regulate Klf4 is needed, or do we need someway to selectively down regulate it in smooth muscle cells?

 

Apparently the researcher selectively down regulated Klf4 in smooth muscle cells. 

 

Global down regulation of this gene might have negative consequences, and it might even undo the effect you're going for.  Then again, if global down regulation works, it might be something you could do on a temporary basis, long enough to clear up these plaques, then allow the expression of this gene to return to normal.  Maybe it would be a treatment you would take periodically.  Say once a year for a month.

 

 

[Lonjaimity]

I'm not sure this is such a head scratcher.  I've seen lots of things come up like this in studies where a cell sort of transdifferentiates temporarily<?> when prompted to do so by external stimuli/irritants.  Here's a very similar one, using similar words, in a similar location.  Actually, the same cells!

 

We, for the first time, showed that in response to the calcified matrix, for both hydroxyapatite crystals and calcified aortic elastin, VSMCs lost their smooth muscle lineage markers and underwent chondroblast/osteoblast-like differentiation. Interestingly, this phenotypic transition was reversible and VSMCs restored their original linage upon reversal of calcification. ("MECHANISMS AND REVERSAL OF ELASTIN SPECIFIC MEDIAL ARTERIAL CALCIFICATION" Yang Lei Clemson University)

 

This is from a researcher studying optimized ways of delivering disodium EDTA to calcifications in arteries with nanoparticle delivery systems and antibodies.  

 

The hope could be that removing the calcium will remove the stimulus and the quasi-bone-quasi-VSMCs will become phenotypically muscular again and commit apoptosis if no longer needed.  Taking K2 probably wouldn't hurt, but removing the calcium using targeted EDTA may be the first step.  The calcium is all in the ECM, so it can be chelated away.

 

I have no idea how difficult it would be to create such a nanoparticle.  The part where he attached EDTA to albumin looks straightforward, but I lose my grasp when he binds it to the antibody.  Importantly, this may tell us that EDTA therapy was never actually complete bull, and it always did something at least marginally useful for some populations.

 

This could be similar to the idea of removing (oxidized) cholesterol from the arteries with something like beta-cyclodextrin.  Maybe once the cholesterol is removed, the VSMC masqerading as macrophages could become phenotypically VSMCs again.  Hopefully after that, they commit apoptosis if they're no longer needed.  Cells do that.  They 'know' based on their surroundings, and signaling around them, what they should be doing and if they're necessary.

 

All theory.  And I think the reversal was in a test tube not vivo.  Even the wording is similar, though, and it's interesting.  Most of this stuff could seem logical.  Beta cyclodextrin succeeds in coaxing cholesterol crystals out of arteries.  (Directed) EDTA helps remove calcification.  Will the phenotypes return to normal when the 'irritants' are gone?

 

The other big missing piece is what instigated it in the first place.  Cholesterol is synthesized in the ER, so it may stem from ER-stress.  A chaperone like TUDCA could prevent it from happening again, and in fact TUDCA has been observed to reduce medial wall thickness and blood pressure ("Attenuating Endoplasmic Reticulum Stress as a Novel Therapeutic Strategy in Pulmonary Hypertension" Peter Dromparis, BSc; Roxane Paulin, PhD; Trevor H. Stenson, PhD; Alois Haromy, MSc; Gopinath Sutendra, PhD; Evangelos D. Michelakis, MD).  RAGE receptors may also have something to do with it.

 

Lots of my armchair science research here, but some looks plausible to me.  I DON'T think this is anything so earth shattering or that it overturns all atherosclerotic theory, though.  And the idea that targeting something downstream or upstream (like regulating expression of KLF4 could be?) does something useful — that's all over the place in medicine.

Edited by Lonjaimity, 17 April 2016 - 12:14 AM.

[PWAIN]

KLF4 looks like it might be a bit dangerous to try messing around with. I am not sure if some sort of targeted Crispr-CAS9 treatment could target just these cells but I don't think promoting or inhibiting KLF4 in the whole body would be safe.