Researchers have found a genetic alteration that slows the progression and fatal consequences of atherosclerosis in a mouse lineage engineered to have an accelerated progression of the disease. As is usually the case in such studies, the primary goal is insight into disease mechanisms, gathering knowledge that may later aid in the development of therapies. It is not necessarily the case that finding a way to slow atherosclerosis in an animal model has relevance to the actual condition: there are many examples of promising research results turning out to be a roundabout way of fixing the breakage in the animal model lineage that causes individuals to develop the condition rapidly and reliably. In normal individuals it then turns out to be useless. This is more often the case in poorly understood areas of biochemistry, given that as knowledge is gained it becomes easier to sift out the more relevant mechanisms, those applicable to the real condition.
Atherosclerosis is a particular unpleasant and prevalent cardiovascular condition that in and of itself causes few overt symptoms until it suddenly kills you. It is an outgrowth of cardiovascular dysfunction in general, however, and is thus usually accompanied by all of the other signs of degeneration in heart and blood vessels: tissue stiffness, hypertension, heart failure, and so forth. The physical damage of atherosclerosis consists of fatty deposits and inflammatory injuries in blood vessel walls, spawned at least in part by the effects of oxidized LDL cholesterol on cell populations in blood vessels, but the increasing stiffness of blood vessel walls and resulting increased pressure of blood flow doesn't help matters by putting additional stresses on these tissues. It is thought that mitochondrial DNA damage is the original cause of much that damaged cholesterol, while the accumulation of persistent cross-links in the extracellular matrix are a primary culprit in blood vessel stiffness.
Once the fatty deposits of atherosclerosis get started, they grow in a positive feedback loop: the damage spurs inflammation, attracting macrophages that attempt to clean up the waste, but which ingest too much fat and become foam cells. These in turn cause more inflammation, produce more fatty debris, and attract more macrophages. The role of inflammation here means that any treatment that reduces the chronic inflammation accompanying aging is likely to be beneficial, but it can't solve the problem. All it can do is slow things down a bit. Prior to the development of self-sustaining fatty deposits, serious damage to blood vessel walls, and restructuring of blood vessels and the heart in response to stiffness and hypertension, it is in principle possible to prevent atherosclerosis and arterial stiffness from ever developing through some combination of SENS therapies targeting mitochondrial DNA damage and cross-links. All the more reason to develop these therapies, but those people already old when they arrive will also need means of safely clearing out the fatty debris of atherosclerotic plaques. That is what kills, when a section finally breaks off to clog a vital blood vessel.
The link below is to the abstract as the full paper, while open access, is still only available in PDF format. It is an interesting look at some of the mechanisms driving the progression of atherosclerosis, and a good example of the way in which most medical research focuses on intervening in later stages of the disease. The proposed intervention here doesn't treat the root causes of the condition at all, but rather seeks to slow down the feedback loop of its later development. As a strategy this will always be less effective and more costly, but here as elsewhere it remains the primary approach for the research community.
Atherosclerosis is one of the major causes of human death in modern society. A high blood cholesterol level resulting from cholesterol metabolism dysfunction is a key known contributing factor for premature atherosclerosis. Using a mouse model of high blood cholesterol, we show that a specific activation marker of a programmed necrosis mediated by the kinase receptor-interacting protein 3 (RIP3) can be detected in the core of atherosclerotic plaques. Mice lacking the RIP3 gene showed a significant reduction of proinflammatory monocytes in the blood and delayed mortality. This study suggests that RIP3-mediated necrotic cell death is part of a self-amplifying proinflammatory cycle that contributes to the premature death of animals with the pro-atherosclerosis trait.
Monocyte cells enter atherosclerotic plaques and subsequently differentiate into macrophages, which, after engulfing cholesterol crystals and becoming foam cells, die in situ to form the necrotic core of the plaques. These dead cells then send out damage-associated molecular patter (DAMP) signals to attract and mobilize more monocytes, completing a vicious cycle that accelerates disease progression. Thus the particular mode of death of these macrophages - apoptosis or necrosis - can be a critical determinant for the initiation of inflammation, because necrotic death releases the cellular contents that constitute the DAMP signal to the blood stream, whereas apoptotic cell debris is engulfed by macrophages without leaking out of the cell.
Recently, the molecular mechanism of a form of programmed cell death termed "necroptosis" was characterized. This form of cell death can be triggered by the TNF family of cytokines and by ligands of Toll-like receptors 3 and 4. The activated TNF receptor recruits receptor-interacting kinase 1 (RIP1) which in turn binds and activates a closely related kinase, RIP3, to form a necrosis-inducing protein complex. The activated RIP3 is marked by phosphorylation that allows it to bind and activate its downstream effector, a pseudokinase known as "mixed lineage kinase domain-like protein," MLKL. MLKL then is phosphorylated by RIP3 and shifts into an oligomerized state that allows it to form membrane-disrupting pores, ultimately resulting in necrotic death.
After we developed a monoclonal antibody that specifically recognizes the phosphorylated RIP3, we studied the role of necroptosis in atherosclerotic plaque areas by using this antibody to probe the signal of necroptosis activation. We further investigated the role of necroptosis in systematic inflammation by analyzing a panel of proinflammatory cytokines and immune cells in ApoE single-knockout and ApoE/RIP3 double-knockout mice. Finally, we addressed the consequences of necroptosis in the animals by comparing the lifespans of ApoE single-knockout and ApoE/RIP3 double-knockout mice fed either a high-cholesterol or a normal diet. It is clear that high blood cholesterol in the ApoE single-knockout mice is sufficient to cause atherosclerotic plaque formation, even without the systematic inflammation contributed by RIP3-mediated necrosis. However, disease progression, as measured by plaque area and thickness, was significantly slowed in the absence of necroptosis. We believe this slowing of disease progression results from an interruption of the vicious cycle of necroptosis-induced inflammation in lesion sites such as atherosclerotic plaques.
The most interesting result from this study is that mice without RIP3-mediated cell death not only manifested much less severe lesions in multiple tissues but also had significantly delayed mortality. What causes necroptosis in the atherosclerotic plaques remains to be determined. It is likely that cholesterol crystals and local higher concentrations of inflammatory cytokines contribute to the death of macrophages. Nevertheless, by using the small molecules specifically targeting necroptosis, which are being developed, it should be possible to alleviate the symptoms and prolong the lives of patients suffering from atherosclerosis.