Lysosomal Dysfunction in Atherosclerosis

Atherosclerosis is the build up of fatty plaques known as atheromas in blood vessel walls, leading to death or injury when blood vessels suffer structural failure or part of a plaque breaks loose to block a blood vessel elsewhere. Plaques start because damaged lipids cause a reaction in blood vessel walls, drawing in the immune cells called macrophages that ingest the lipids to remove them. Sometimes this doesn't work well enough, and the immune cells become stressed by intake of too many lipids and die. Plaques are comprised of the remnants of cells, and the presence of all this waste material causes further inflammation, producing a vicious cycle in which the plaques grow by attracting ever more immune cells.

This is a process that can be sped up by a number of factors, such as greater chronic inflammation or more lipids damaged by oxidation due to higher levels of oxidative stress in tissues. Both of these occur with aging and as a result of conditions such as obesity known to raise the risk of suffering atherosclerosis. Another item to consider is the degree to which immune cells are capable of digesting lipids. These molecules should be broken down in the cells' lysosomes, but lysosomal function is another aspect of cell biology that deteriorates with age.

Here, researchers show that spurring macrophages to generate more new lysosomes in reaction to the stress of ingesting lipids slows the development of atherosclerosis, which is much as expected. Even if they lysosomes are dysfunctional, more of them should still improve this particular situation:

Recent reports of a proatherogenic phenotype in mice with macrophage-specific autophagy deficiency have renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique ability to process both exogenous material, including lipids and autophagy-derived cargo such as dysfunctional proteins/organelles. We aimed to understand the effects of an atherogenic lipid environment on macrophage lysosomes and to evaluate novel ways to modulate this system.

Using a variety of complementary techniques, we show that oxidized low-density lipoproteins and cholesterol crystals, commonly encountered lipid species in atherosclerosis, lead to profound lysosomal dysfunction in cultured macrophages. We find that macrophages isolated from atherosclerotic plaques also display features of lysosome dysfunction. We then investigated whether enhancing lysosomal function can be beneficial. Transcription factor EB (TFEB) is the only known transcription factor that is a master regulator of lysosomal biogenesis although its role in macrophages has not been studied. Lysosomal stress [leads] to TFEB nuclear translocation and activation of lysosomal and autophagy genes. TFEB overexpression in macrophages further augments this prodegradative response and rescues several deleterious effects seen with atherogenic lipid loading.

Taken together, these data demonstrate that lysosomal function is markedly impaired in atherosclerosis and suggest that induction of a lysosomal biogenesis program in macrophages has antiatherogenic effects.


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