Atherosclerosis is the number one killer in the world, and science is working on solutions to combat this age-related disease. A new mouse study has shown that the drug trodusquemine can melt away the accumulated arterial plaques that lead to heart attacks and strokes.
What is Atherosclerosis?
Atherosclerosis is an age-related disease in which toxic, oxidized cholesterol deposits in the bloodstream produce inflammation in arterial walls. This causes macrophages to swarm to these fatty deposits to clear up this toxic waste.
Unfortunately, our macrophages are not as robust as we would like them to be, and over time, they gobble up so much waste that they either die immediately or become senescent and turn into foam cells.
Foam cells are dysfunctional macrophages that increase inflammation and have become embedded in arterial walls. This rising inflammation works like an alarm system and summons more macrophages to the injury site, and they also succumb to the same fate over time.
Another problem is that, as we age, the immune system declines, and, again, this causes macrophages to increasingly become dysfunctional and stop working properly. They increasingly favor an inflammatory behavior over a healing one.
Ultimately, this build-up of dead and dying macrophages is the basis of the plaques that lead to atherosclerosis. They build up and eventually rupture, causing clots to break off, which leads to heart attacks and strokes.
All humans have some level of atherosclerosis, regardless of lifestyle and diet. As you age, you start to develop fatty deposits inside your arteries. If you live long enough, these deposits will become a problem.
A research team from the University of Aberdeen showed that a single dose of trodusquemine was able to completely reverse the effects of the disease in just a single dose in mouse models of heart disease.
In the mouse study, model mice with atherosclerosis had less plaque in their arteries when they had regular doses of trodusquemine or just a single dose. The drug works by blocking an enzyme called tyrosine-protein phosphatase non-receptor type 1 (PTP1B), which is normally elevated in people with obesity, diabetes and inflammatory conditions, such as sepsis, allergic lung inflammation, and diabetic foot ulcers.
The researchers discovered that blocking PTP1B also stimulated the protein AMP-activated protein kinase (AMPK). This is one of the central regulators of cellular and organismal metabolism in cells, and it is activated when intracellular ATP (cell energy) lowers.
AMPK plays key roles in regulating growth and reprogramming metabolism, and it is connected to cellular processes such as autophagy and cell polarity (like a cellular program which determines cell behavior). AMPK stimulation is also similar to the effects of exercise and reduces chronic inflammation.
Trodusquemine is already in trials
Trodusquemine is currently in phase 1 trials for breast cancer, but this is the first time the drug has been tested in animal models of atherosclerosis. So far, the results have been quite impressive and showed that a single dose of the drug appears to completely reverse the effects of atherosclerosis.
The next step will be to move to human clinical trials to see if this drug can improve patient outcome in humans with atherosclerosis. Given that a number of other phase 1 trials for trodusquemine have been conducted, this may contribute to supporting evidence of safety and potentially speed up the process.
The study shows that it not only reverses atherosclerosis but can also reduce the build-up of the fatty deposits that lead to the formation of plaques. If the same effects are observed in human trials, this could mean the drug could be an effective preventative as well as a treatment for atherosclerosis.
The approach here appears to slow the pace at which macrophages arrive at the injury site only to be overwhelmed and contributing to the very plaques they are trying to remove. The researchers here demonstrate that by blocking PTP1B, they can reduce inflammation and block the signals that summon more macrophages to the injury site.
This has the effect of breaking the vicious cycle of inflammation, macrophage arrival, and macrophage death enough to allow natural mechanisms to reduce the plaques already in situ. This has the effect of reversing the development of atherosclerosis.
The damage repair approach to aging makes removing these accumulated plaques one of the key things we need to do in order to combat age-related diseases. For example, SENS aims to find bacterial enzymes capable of digesting these fatty deposits, and these enzymes can then form the basis for drug development. Other groups are testing adjusting macrophage behavior so that they facilitate healing rather than inflammation.
The bottom line here is that all these techniques are viable, and each is a potential path to achieving the goal of removing plaques. Ultimately, it is irrelevant which approach is used to do this; the only thing that matters here is that it works. The end result is what is important, not how it’s achieved.
Finally, the usual caveats apply here; this is a mouse trial, and we will need to see if the results translate during clinical trials. If they do, then this could be a solution to the biggest killer disease in the world.
 Thompson, D., Morrice, N., Grant, L., Le Sommer, S., Lees, E. K., Mody, N., … & Delibegovic, M. (2017). Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR−/− mouse model of atherosclerosis. Clinical Science, 131(20), 2489-2501.