Macrophage Dysfunction is the Important Target if Seeking to Treat Atherosclerosis
Atherosclerosis is characterized by the formation of fatty plaques in blood vessel walls, narrowing and weakening vessels. It leads to heart failure, as well as heart attack and stroke as the result of rupture of a blood vessel or plaque. Near all treatments for atherosclerosis are preventative, which is the better approach to medicine, and are focused on the outcome of lowering LDL cholesterol in the bloodstream, which is, unfortunately, not the better approach to atherosclerosis.
Atherosclerosis is, at root, a condition caused by macrophage dysfunction. Macrophages are the innate immune cells tasked with clearing debris from blood vessel walls. That debris includes errant cholesterol. Cholesterol is needed everywhere in the body, but is expensive to produce, and is only made in a few places, primarily the liver. Cells do not break down excess cholesterol, but rather traffic it around the body as needed via the bloodstream. Cholesterol made in the liver is attached to LDL particles and sent out into the body. Macrophages serve a vital function in returning excess cholesterol from blood vessel walls to the bloodstream, attaching it to HDL particles which return to the liver.
This complicated system works just fine in youth, but macrophages become dysfunctional with age, faltering in their task of cholesterol uptake and hand-off to HDL particles. This is thought to be largely an issue of rising levels of forms of oxidized and otherwise altered cholesterol, a consequence of oxidative stress and metabolic dysfunction in aged tissues. Macrophages are poorly equipped to process altered cholesterol, and become overwhelmed and inflammatory. Another contributing issue is a rising level of background inflammation, caused by immune system reactions to signs of age-related molecular damage in the body, among other causes. Macrophages can adopt different behaviors depending on their environment: the M2 phenotype is suitable for clearing out cholesterol from blood vessel walls, but inflammatory signaling provokes macrophages into the M1 phenotype instead.
The result is that atherosclerotic plaques become inflammatory hotspots of dysfunctional, dying macrophages. Their distressed signaling calls in more macrophages, forming a positive feedback loop that will proceed once established regardless of levels of LDL cholesterol in the bloodstream. Lowering LDL cholesterol takes some of the pressure off macrophages, and can result in a reduction of lipids in the worst plaques, but it has only a limited success in reducing mortality precisely because it doesn't reverse development of plaques to a meaningful degree. To do better than this, the macrophages must be rescued, made invulnerable (or at least more resilient) to the factors causing them to become dysfunctional. If macrophages in old tissues worked in the same was as they do in young tissues, there would be no atherosclerosis. Both Underdog Pharmaceuticals and Repair Biotechnologies are working on approaches to this goal.
A number of research groups also work towards improving macrophage function as an approach to the treatment of atherosclerosis, but not all such efforts are likely to be meaningfully effective. Metformin, for example, the subject of today's open access paper, influences some mechanisms of interest, such as those relating to inflammatory signaling. We know what the outcomes of metformin use on mortality are in humans, however, and they are certainly not good enough to justify a strong focus on this drug. Whether it can point the way to more effective treatments that target the same signaling mechanisms is an open question.
Metformin, Macrophage Dysfunction and Atherosclerosis
Metformin is one of the most widely prescribed hypoglycemic drugs and has the potential to treat many diseases. More and more evidence shows that metformin can regulate the function of macrophages in atherosclerosis, including reducing the differentiation of monocytes and inhibiting the inflammation, oxidative stress, polarization, foam cell formation, and apoptosis of macrophages. The mechanisms by which metformin regulates the function of macrophages include AMPK, AMPK independent targets, NF-κB, ABCG5/8, Sirt1, FOXO1/FABP4, and HMGB1.
Macrophages, which are distributed in the circulation and tissues and aggregate under a variety of pathological conditions, can play an important role in a variety of diseases by regulating inflammation. Considerable evidence indicates that metformin can improve the dysfunction of macrophages which is a cause of atherosclerosis. We speculate that improving the function of macrophages may be the basis for the expanding therapeutic potential of metformin. Combined with other drugs that improve the function of macrophages (such as SGLT2 inhibitors, statins, and IL-β inhibitor), this may help to further strengthen the pleiotropic actions and thus the therapeutic potential of metformin.
In addition, there is evidence that metformin can inhibit the formation of neutrophil extracellular traps (NETs), which may be related to the effect of metformin on improving macrophage function. In terms of research depth, single-cell sequencing helps to further clarify the mechanism of metformin and help to discover new targets for improving the function of macrophages and controlling or reducing the role of these cells in multiple disease processes and states.
hromosomal instability is a feature of solid tumors such as carcinoma. Likewise, cellular senescence is a process that is highly related to cellular aging and its link to cancer is becoming increasingly clear. Scientists led by ICREA researcher Dr. Marco Milán at IRB Barcelona have revealed the link between chromosomal instability and cellular senescence.
"Chromosomal instability and senescence are two characteristics common to most tumors, and yet it was not known how one related to the other. Our studies indicate that senescence may be one of the intermediate links between chromosomal alterations and cancer," says Dr. Milan, head of the Development and Growth Control laboratory at IRB Barcelona.
"The behavior we saw in cells with chromosomal instability made us think that they could be senescent cells, and indeed that was the case," says Dr. Jery Joy, first author of the article published in Developmental Cell.
The study has been conducted on the fly Drosophila, an animal model commonly used in biomedicine, and the mechanisms described may help to understand the contribution of chromosomal instability and senescence to cancer, and facilitate the identification of possible therapeutic targets.
Somewhat off topic, relevant to general health and endothelial condition.
Ya we need the technology you are working on that pulls the cholesterol out of the artery walls and then lets the arteries heal.
It is nice to see actual smart people on this.
Most of big pharma is like the usual large bureaucracies and very resistant to new ideas.
Something I learned about scientists is most of them are capable at their jobs if you tell them exactly what you want them to do. But maybe less than 1 in thousands are discoverers, who will come up with new ideas and want to try 10 other things.
So those regular scientists are valuable when combined with a discoverer.
I hope your cholesterol project is successful Reason. As far as the text book claim 'all cholesterol is made in the liver' , every cell in the body can make cholesterol. It seems to me the cells probably do make cholesterol but research has not quantified this yet.
This scientist is suggesting the current prevailing hypothesis is not based on real knowledge:
The consensus hypothesis on coronary atherosclerosis suggests high LDL-C levels as the major cause and pursues it as the therapeutic target, explicitly assuming: (i) tunica intima of human coronaries consists of only one cell layer - endothelium, situated on a thin layer of scarcely cellular matrix; and (ii) subendothelial lipoprotein retention initiates the disease. Facts showed: (i) normal tunica intima invariably consists of multiple cellular layers; and (ii) initial lipid depositions occurred in the deepest layers of tunica intima. This review suggests that coronary atherosclerosis starts with pathological intimal expansion, resulting in intimal hypoxia and neovascularization from adventitial vasa vasorum, facilitating lipoprotein extraction by previously avascular deep intimal tissues. Until the hypothesis incorporates real knowledge, our efforts will probably be off-target."
"Excessive intimal hyperplasia in human coronary arteries before intimal lipid depositions is the initiation of coronary atherosclerosis and constitutes a therapeutic target
Vladimir M Subbotin 1"