Reassessing Smooth Muscle Cells in Atherosclerosis

Over the last few years researchers have gathered data that suggests smooth muscle cells have a more important role in the later stages of atherosclerosis than previously suspected. This new result adds to the evidence:

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.

Recent 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. 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."

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 and it has led to "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.)

Researchers identified a key gene, Klf4, that appears to regulate these transitions of smooth muscle cells. Remarkably, when Klf4 was selectively knocked out 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.



KLF4 could be a therapeutic target to clear plaque judging by the results here, a small molecule or transient gene therapy could be delivered to the plaque to reduce inflamation and pave the way for additional regenerative therapy. Perhaps KLF4 is something for SENS to investigate if they are not already doing so? The accumulated junk the body cannot clear due to dysfunctional cells/bad gene expression is a problem common to both aging camps and needs solving.

Posted by: Steve H at July 7th, 2015 7:43 AM

For dealing with the problem before it occurs IMO it is down to the cells losing their ability to express the correct genes. This is in part through epigenetic changes via telomere attrition/TPE and damage. Now to me the logical thing would be to attempt to restore youthful gene expression/function via restoration of telomeres. However there is concern that rejuvenating SMCs may cause plaque to become unstable. I asked Dr Fossel about this potential problem, I hope he will not object to me posting his comments here:

"Your question regarding plaques is a good one and the answer is (not surprisingly) complex. The simple answer, however, is well established by the data and suggests that telomerase works quite nicely in both tissues (in vitro) and in animals (in vivo) with good results. To get to the complex part, however, there are two conflicting processes at work and the practical question is which one is the greater risk or the greater benefit in the balance? On the one hand, we know that endothelial cell telomere shortening precedes (and “causes”) the vascular lesions as the endothelial cells change their pattern of epigenetic expression, resulting in subendothelial dysfunction, etc. On the other hand, the response of macrophages (and other cells) is rapid division and inflammation with many of these cells newly recruited from the marrow (hence the positive telomerase). The question is “what happens if we increase the telomeres of all of these cells, i.e., both endothelial cells and macrophages. The answer (as above) is that things get better. One final complication might be that some of the cells (macrophages perhaps?) may actually be senescent and re-expressing telomerase, much like some cancer cells. While that sounds fine, if they don’t express enough telomerase to extend telomeres substantially, then they simply muddle along with telomerase and barely-maintained telomeres, a poor pattern of gene expression, and they cause additional damage. In short, if they just express enough telomerase to maintain short telomeres (rather than relengthening their telomeres fully), then they are simply prolonging the pathology. IF, however, we give telomerase (e.g., by AAV) and fully re-extend telomeres, then we would expect the pathology to improve, which is what actually happens.

One last caveat: even if we do fully extend telomeres, the arteries will take a while to clear up and the patient can still undergo a fatal thrombotic or embolic event while waiting to get better."

Either way if you agree with him or not plaque removal should be a priority in any regenerative medicine approach. It would be better to avoid the problem in the first place but for those of us reading this now the problem is already underway to a greater or lesser degree. I suspect we will need some way to remove the accumulated plaque aside from any attempt to rejuvenate SMCs etc.. As I said above this is a common ground shared by both aging theory camps.

Posted by: Steve H at July 7th, 2015 7:49 AM

@Steve - The heart attacks being referred to here are caused by oxidised LDL accumulating in macrophages in the blood vessel walls. The oxidised LDL accumulates not due to epigenetic or genetic changes in the macrophages, but because they have never been able to process it. You could try and use gene therapy to create macrophages with the enzymes (adopted from bacteria) to process oxidised LDL, but the SENS foundations approach of simply targeting these enzymes to the blood vessel macrophages is probably simpler and more controllable.

Posted by: Jim at July 7th, 2015 2:22 PM

@Ray - I do not agree that the body cannot process this at all but I do agree that it is unable to process it fully, otherwise why does plaque formation speed up with age? The body obviously does resist it when in better working order and expressing a youthful gene profile.

But anyway more importantly I agree that this junk needs removing as part of any regenerative medicine attempt. The more important issue here is it needs removing. Now perhaps SENS might develop something in the near future or someone else will. Does not really matter as long as someone works out how to do this.

Knocking down Klf4 transiently in the target cells is a viable route to achieving this, it is unlikely AAV would be useful for this according to a friend of mine who works in the gene delivery field and suggests sRNA would probably do this better. SENS route of removing the cells is also a good idea and should be pursued as high priority considering the havoc plaque wrecks on the body.

Posted by: Steve H at July 8th, 2015 2:02 AM

Also if the body does not clear or reduce the build up of plaque through internal systems how is that Progeria children have extensive plaque build up and abnormally short telomeres and die in a very short time often due to build up of plaque? If the body was incapable of mitigating any of the build up and was not clearing any of it then logically we would all die in our early twenties from the same thing. However we have normal telomeres and gene expression and we do not die from the same build up of plaques early in life.

Posted by: Steve H at July 9th, 2015 4:01 AM

Steve H, I can think of several reasons why plaque formation speeds up during aging that don't involve telomere length or genetic/epigenetic changes. One reason is that as plaque accumulates, even more macrophages are attracted to the lesion, and this generates even more plaque at an ever increasing rate. Even if the macros could initially digest the oxidized cholesterol, their ability to digest it diminishes probably due to the massive amounts that need to be processed, and so, they become foam cells. A second reason might be that as mitos increase free radical production during aging this may increase the rate at which cholesterol oxidises and thus speed up plaque formation.

The plaque buildup in progeria patients is a lot different than the plaque buildup in normal people. The rapid formation of plaque in progeria patients seems to be due to the thinning of blood vessel walls caused by cell senescence.

Posted by: Florin Clapa at July 9th, 2015 1:22 PM
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