Discusses how Protein Cycling might prevent cardio-vascular diseases
Phagocytes are the class of cells that perform phagocytosis, an invagination of the outer cell membrane that envelops external solid material (>0.75 um by definition) in much the same way as autophagy envelops internal material. The liposomes so formed, phagosomes, are often processed in the same way as autophagosomes, namely by fusion with lysosomes. It is thought that most cells (excepting perhaps extremely specialized cells such as nerves, muscle and red blood cells) can at least phagocytose their dead neighbors, and so the term, professional phagocyte is applied to those cell types for which phagocytosis is their main function. These cell types comprise a dizzying array of named forms differing in their purpose, location, mobility and maturation, but, for this topic, only the macrophage, its precursor the monocyte, and its senescent form the foam cell need be considered. Monocytes are white blood cells that leave the blood stream and enter tissue when invited where they transform into macrophages (big eaters). If they then overeat on oxidized fats, they can transform into foam cells.
Atherosclerosis is a specific form of arteriosclerosis (lit. hardening of the arteries) in which foam cells play a central role. It begins when cholesterol deposits between the cells of the inner lining of an artery and the layer of smooth muscle around them forming a so-called plaque. Oxidation of this fat causes the epithelial cells lining the artery to signal its presence and thus draw in monocytes from the circulating blood to clear it up96. The monocytes then transform into macrophages and start eating. Human cells, though capable of producing cholesterol, are incapable of breaking it down. Instead excess cholesterol is transported by a particular protein in the blood (as HDL) to the liver where the cholesterol is deposited in the bile as bile salts. By this process, the plaque is cleared up, the macrophages eventually die or emigrate90 and no trace of the cholesterol deposit remains.
At least that is what is supposed to happen. Instead the fat seems to enter the macrophages at a greater rate than it can be processed and exported. The fat droplets accumulate in the constipated macrophages which are then designated as foam cells95. These foam cells are unable to extricate themselves from the plaque and so they expand and weaken it as they accumulate and die. Rupture of the weakened plaque can then release solid matter that then blocks the artery causing a heart attack if in the heart, a stroke if in the head or thrombosis generally anywhere in the body.
It is now known that the ingested fat droplets are normally processed in the macrophage by autophagy92 and that this process is the rate limiting step in cholesterol export. Perhaps this accumulation of fat droplets arises from a failure of the macrophages to initiate and complete autophagy to clear them out. Perhaps the macrophages are depending on the usual fasting episodes of the organism to complete the process, and the high incidence of cardiovascular diseases, like neurodegenerative diseases, may arise from the extinguishing of routine fasting in industrial societies. If so then protein cycling should work to clear artherosclerotic plaque and prevent most heart disease, statistically a far more significant outcome based on mortality rates than preventing neurodegenerative diseases.
Is there any evidence to support this hypothesis? There is some argument in the current literature as to whether autophagy is helpful or harmful in atherosclerosis94. If autophagy is indeed helpful then things that promote autophagy such as ADCR and rapamycin should show some positives:
Smooth muscle cells, another component of plaque, are seen to be protected from cell death by cholesterol overload by rapamycin. The opposite occurs with the autophagy inhibitor, 3-methyl adenine93.
Other studies have shown that autophagy promotion enhances the ability of heart cells to recover from a brief period of oxygen starvation as happens in the cardiac artery blockage of a typical heart attack. A similar protective benefit is seen in brain tissue and stroke97.
The heart muscle itself can be the site of origin of cadiovascular disease. Heart muscle cells, like most human cells, are differentiated to perform a specific task and, as a result, have lost the ability to divide and multiply. The heart, like most organs and muscles, keeps a population of undifferentiated stem cells to replace any cells that die, though in the heart’s case, the few if any stem cells present appear inadequate to handle even a moderate die-off. In consequence heart muscle cells are like neurons; their life span matches the organism’s life span and are not renewed and rejuvenated sufficiently by cell division. Cellular junk that the cell cannot dump can accumulate over the decades to the point of interfering with normal operations. Lipofuscin is the name give the most prominent junk in human cells. It is what remains in the lysosome after all that can be digested has been digested. It consists mostly of cross-linked oxidized unsaturated fatty-acids and proteins entrapping metals, sugars, etc notably aluminum and iron. One would think the cell would just dump it by exocytosis to be picked up by macrophages who would then migrate to the liver or spleen to dump it into the bile. Some studies suggest that something like this indeed happens105 Others suggest otherwise, that the lipofuscin just accumulates in the cell106. Regardless, its accumulation is a hallmark of old age and may ultimately cause heart failure. Calorie restriction diets have been shown to reduce lipofuscin107 and enhanced autophagy may be the mechanism, yet another way in which protein cycling could be heart protective.
In summary, protein cycling has the potential to diminish cardiovascular disease in three ways: by promoting cholesterol export from atherosclerotic plaque, by enhancing heart muscle recovery from temporary oxygen starvation, and by reducing lipofuscin accumulation in heart cells.