In the paper I'll point out today, the authors provide evidence in support of the concept that it is specifically oxidized cholesterol that is the primary cause of atherosclerosis rather than the condition resulting from too much cholesterol in general. In atherosclerosis, fatty deposits form in blood vessel walls, weakening them and narrowing the vessels. This ultimately leads to fatal structural failure as stressed blood vessels rupture or are blocked. Atherosclerosis is arguably a condition that arises because the macrophages responsible for removing cholesterol from blood vessel walls become overwhelmed, inflammatory, and incapable of keeping up the work of maintenance and repair. They become foam cells and die, adding their contents and their remnants to grow an atherosclerotic plaque, and attracting more of their fellows to the same location to repeat the cycle.
Here it is argued that this foam cell fate is largely the consequence of oxidized cholesterol. The macrophages are reacting to oxidized cholesterol in ways that sabotage their efforts to remove local deposits of cholesterol. The approach to this condition adopted by the SENS rejuvenation research programs is to find ways to break down the oxidized cholesterol that our cells struggle to deal with. Removing it from the picture should enable cells to continue as they were, and remove the fatty deposits. Researchers associated with the SENS Research Foundation have searched for bacteria capable of consuming these damaged forms of cholesterol, in order to adapt their enzymes into therapeutic molecules. This work has to date largely focused on 7-ketocholesterol, with some early success, but a broader and more heavily funded research program is very much called for.
One of the main characteristics of atherosclerosis is the accumulation of lipids in the intimal layer of the arterial wall. In atherosclerotic plaques, phagocytic cells, such as macrophages, engulf atherogenic low-density lipoprotein (LDL) particles, but are unable to process them, and thus become foam cells, having cytoplasm packed with lipid droplets. Foam cells are characterized by several typical features: they have decreased ability to migrate, while displaying enhanced production of pro-inflammatory cytokines. Therefore foam cells participate in maintaining chronic inflammation in the lesion.
Previous studies have shown several clusters of genes up- or down-regulated in macrophages in response to oxidized LDL, which is known to be atherogenic. Regarding the inflammatory response, modified LDL appeared to trigger up-regulation of genes with anti-inflammatory activities. We performed a transcriptome analysis of macrophages treated with atherogenic LDL that causes intracellular cholesterol accumulation. We used the strategy of upstream analysis for causal interpretation of the expression changes.
In this study, we discovered 27 transcription factors that were potentially responsible for the changes in gene expression induced by modified atherogenic LDL. These transcription factors were used for identifying the master-regulators (genes and proteins) responsible for regulation of large cascades of differentially expressed genes. In general, the genes that were up-regulated in response to lipid accumulation in macrophages induced by atherogenic LDL were mostly involved in inflammation and immune response, and not in cholesterol metabolism. Our results suggest a possibility that it is not cholesterol accumulation that causes an innate immunity response, but rather the immune response is a consequence of a cellular reaction to modified LDL. These results highlight the importance of the inflammatory component in the pathogenesis of atherosclerosis.
A hallmark of atherosclerosis is its complex pathogenesis, which is dependent on altered cholesterol metabolism and inflammation. Both arms of pathogenesis involve myeloid cells. Monocytes migrating into the arterial walls interact with modified low-density lipoprotein (LDL) particles, accumulate cholesterol and convert into foam cells, which promote plaque formation and also contribute to inflammation by producing proinflammatory cytokines. A number of studies characterized transcriptomics of macrophages following interaction with modified LDL, and revealed alteration of the expression of genes responsible for inflammatory response and cholesterol metabolism. However, it is still unclear how these two processes are related to each other to contribute to atherosclerotic lesion formation.
We attempted to identify the main master regulator genes in macrophages treated with atherogenic modified LDL using a bioinformatics approach. We found that most of the identified genes were involved in inflammation, and none of them was implicated in cholesterol metabolism. Among the key identified genes were interleukin (IL)-7, IL-7 receptor, IL-15, and CXCL8. Our results indicate that activation of the inflammatory pathway is the primary response of the immune cells to modified LDL, while the lipid metabolism genes may be a secondary response triggered by inflammatory signalling.