Slowing Atherosclerosis Development By Interfering in the Reaction to Disturbed Blood Flow

Much of modern medicine does not address root causes. If there is one clear item that has to change in order for the research community to effectively address degenerative aging, it is this. It is perhaps understandable as to how we find ourselves in this position: most research into specific diseases starts at the end point, with the full-blown late-stage manifestation of the condition, and works backwards from there. The role of the research has long been to understand what is going on at the level of cells and proteins in the late stages of disease, and then trace back the chain of relationships and interactions to earlier stages. Thus progress leads into the middle stages of cause and effect, and most potential treatments built using modern tools of biotechnology tend to be ways to interfere in proximate causes, not root causes. The people who catalog root causes and work on ways to repair them, aiming to prevent large numbers of medical conditions with a small number of treatments, are still a small minority in medical research, unfortunately.

This is a good example of the sort of thing I'm talking about here: it doesn't address the reasons why blood flow becomes disturbed, but seeks to decouple that from a raised risk of atherosclerosis. This will be beneficial if it works, but it does nothing to address the real issues or the other problems that said issues causes.

In atherosclerosis, plaques preferentially develop in arterial regions of disturbed blood flow (d-flow), which alters endothelial gene expression and function. Here, we determined that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase-dependent (DNMT-dependent) manner.

Induction of d-flow by partial carotid ligation surgery in a murine model induced DNMT1 in arterial endothelium. In cultured endothelial cells, DNMT1 was enhanced by oscillatory shear stress (OS), and reduction of DNMT with either the inhibitor 5-aza-2′-deoxycytidine (5Aza) or siRNA markedly reduced OS-induced endothelial inflammation. Moreover, administration of 5Aza reduced lesion formation in 2 mouse models of atherosclerosis.

We determined that d-flow in the carotid artery resulted in hypermethylation within the promoters of 11 mechanosensitive genes and that 5Aza treatment restored normal methylation patterns. Of the identified genes, HoxA5 and Klf3 encode transcription factors that contain cAMP response elements, suggesting that the methylation status of these loci could serve as a mechanosensitive master switch in gene expression. Together, our results demonstrate that d-flow controls epigenomic DNA methylation patterns in a DNMT-dependent manner, which in turn alters endothelial gene expression and induces atherosclerosis.



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