Recent Investigations into the Mechanisms of Atherosclerosis

Atherosclerosis is a particularly unpleasant age-related condition not because it causes great suffering along the way but because it is comparatively invisible right up until the point at which it kills you suddenly. In atherosclerosis the blood vessel walls are thickened by material that is largely composed of immune cells and the fatty remnants of dead cells. Eventually this material becomes unstable enough to cause major blood vessel failure or for a piece to break off and catastrophically block a blood vessel elsewhere in the body, leading to stroke or heart attack.

Once atherosclerotic plaques exist in earnest, they become a ongoing industry of inflammation, cell death, and restructuring on the inside of your blood vessels. The immune cells present in the area act to maintain inflammatory conditions that help to make things worse and attract more immune cells, creating an ever larger mess as time goes by. The starting point for this process involves cholesterols, however. Low-density lipoproteins (LDL) can become damaged by oxidative reactions and in large enough numbers their presence causes a response in blood vessel walls, wherein the tissues issue a call for immune cells to turn up and remove the unwanted damaged LDL molecules. Sometimes this all proceeds according to plan and the harmful LDL is removed, but sometimes the immune cells cannot cope with the ingestion of LDL and die. This can snowball into precursor fatty structures that will grow to become atherosclerotic plaques.

So progression of atherosclerosis is one of the many aspects of aging that can be sped by an environment of greater chronic inflammation in the body. But it is also driven by levels of damaged LDL. That second item is the link between causes of chronic oxidative stress in tissues, rising levels of oxidative molecules roaming to cause unwanted reactions and damaged proteins, and damage such as that of atherosclerosis. Damage caused to mitochondria over the course of aging in particular is thought to drive rising levels of oxidative molecules such as reactive oxygen species: some cells in every tissue become very dysfunctional as a result of this, overtaken by damaged mitochondria and turned into exporters of oxidative molecules. That flow of oxidative molecules can react with and damage important proteins such as LDL that travel far in the body via the circulatory system - and thus contribute to the roots of atherosclerosis over the years.

So I've sketched a picture here, but the reality is that these are complex mechanisms and in absence of repair technologies to remove one or another contribution to atherosclerosis it is hard to prove the degree to which various different sources contribute to the pathology of the condition. For example, there are other ways to modify LDL so as to cause pathology, but this is all the more reason to work harder on repair biotechnologies, as I see it. They are an investigative tool that compares favorably in projected cost and time at this point in comparison to the slow and painfully expensive approach of gathering a full understanding of any process in the aging of metabolism. That all said, here is an example of present research aimed at improving understanding of the causes of atherosclerosis, a paper that touches on some of those other means to alter LDL in harmful ways:

New immunological findings provide possible therapy for cardiovascular disease

Atherosclerosis is an inflammatory process where lipids in the form of LDL cholesterol (also called 'bad cholesterol') are stored in the artery walls. The activation of the immune system in the form of T-cells, among others, plays a vital role, particularly for rupturing the atherosclerotic plaques which, the primary cause of myocardial infarction and stroke. LDL is only taken up in the artery wall after modification, a process where oxidation is one probable underlying cause. Enzymes in the artery walls can also modify LDL making it inflammatory. Most basic scientific studies in the field are based on mouse models with genetic changes as mice cannot develop arteriosclerosis or cardiovascular disease.

[The researchers] studied inflammatory and immune defence reactions in atherosclerosis and cardiovascular disease using plaque cells and blood from patients with cardiovascular disease. The researchers have observed that the lipids (phospholipids) in modified LDL appear to be one of the primary causes. The research team has shown that LDL that is modified by enzymes in the artery walls can activate dendritic cells, which in turn play a key role in activating the T-cells. Non-modified, regular LDL on the other hand had no effect on these cells in the study. The research also indicates the possible existence of a mechanism, namely that stress proteins (also called heat shock proteins) are expressed, which is decisive when modified LDL activates the dendritic cells and T-cells. The study shows that a plasma protein Annexin A5 decreases inflammation and modulates immune reactions to modified LDL, which creates a protective effect.

Induction of Dendritic Cell-Mediated T-Cell Activation by Modified but Not Native Low-Density Lipoprotein in Humans and Inhibition by Annexin A5

Atherosclerosis is an inflammatory disease, where activated immunocompetent cells, including dendritic cells (DCs) and T cells are abundant in plaques. Low-density lipoprotein modified either by oxidation or by human group X-secreted phospholipase A2 (LDLx) and heat shock proteins (HSP), especially HSP60 and 90, have been implicated in atherosclerosis.

We previously reported that Annexin A5 inhibits inflammatory effects of phospholipids, decreases vascular inflammation and improves vascular function in apolipoprotein E−/− mice. Here, we focus on the LDLx effects on human DCs and T cells. Our data show that modified forms of LDL such as LDLx but not native LDL activate human T cells through DCs. HSP60 or 90 contribute to such T-cell activation. Annexin A5 promotes induction of regulatory T cells and is potentially interesting as a therapeutic agent.

You can clearly see the standard research approach here: look for ways to interfere in the details of the process of development (tinker with levels of Annexin A5 to try to reduce the inflammation levels caused by the presence of damaged molecules) rather than address the root cause (the presence of that damaged LDL in the first place). When you work from the end state backwards, points at which the process might be altered are the first things to be discovered. That doesn't mean it is a good approach, however. What it means is that it is the approach most likely to win further funding and a prospect of entering the drug development and regulatory pipeline as they are presently instantiated. Effectiveness of the research strategy as a whole is a much lower priority, sad to say.


The proposed mechanisms causing atherosclerosis have serious flaws. Specifically, "...The starting point for this process involves cholesterol..." ignores that many people with extreme levels of LDL never develop any atherosclerotic plaque at all. I have spent considerable effort asking researchers for hypotheses why, to use my specific example, my 69 year old arteries, that have been subjected to extreme levels since birth, are completely free of calcified plaque (latest EBCT score was again zero). How can an LDL of, say 125mg/dl, of itself, be a problem when I can have an LDL for the last 8 years of over 500? My family history shows no evidence of early deaths or heart attacks.

The usual response I get is that "its in the genes". That means nothing at all, since, of course, everything is always in the genes. What genes? What mechanisms? How do the genes influence arterial activity? No one knows and no one seems interested in finding out. After 50 years of being involved with FH it seems that there still is no clear mechanism describing plaque formation, why it occurs in isolated locations, why it doesn't occur in some people with extreme levels of LDL, why it does occur in some people with low levels of LDL? The questions go on and on and never seem to get addressed.

Additionally, the relative frequency of occurrence, by genetic anomaly standards, of FH says a lot about how hazardous extreme LDL levels are (or are not!) How can an allele that raises LDL levels so much above the norm be so detrimental and yet still occur at the rate of one in five hundred? That equates to 14 million people worldwide having HeFH! The harsh reality is that if a gene for extreme LDL were even ten percent less successful at producing offspring, the gene would be gone from the gene pool in an evolutionary blink of an eye. That's just an unassailable mathematical fact. Yet here it is; given its existence throughout the world it has more than likely been around for a long time.

Cholesterol is a very complex molecule and even though it takes many, many steps to produce, it is produced by virtually all cells because it is needed by all cells. The liver makes cholesterol for the rest of the body, but if liver cholesterol does not get into a cell, the cells do it themselves. The brain is a major user of cholesterol; all the grey matter is essentially pure cholesterol. We have the biggest brains of any primate so it is no wonder we need lots of cholesterol. Drugs that lower cholesterol affect the ability of glial cells to produce cholesterol for the brain, and, unfortunately, lipids from the liver cannot cross the blood/brain barrier, so the brain may be seriously deprived of necessary cholesterol. That cannot be a good idea.

Posted by: RWBramel at June 22nd, 2015 3:56 PM

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