Atherosclerosis as a Localised Amyloid and Proteostasis Disorder

Le résumé fourni par la source

Atherosclerosis and atherosclerotic plaque formation underpin a variety of acute cardiovascular events including myocardial infarction and ischaemic stroke, and vascular diseases of this type are effectively the leading causes of death worldwide. Despite the presence of many proteases that are normally capable of degrading the proteins that these plaques contain, the existence of atherosclerotic plaques necessarily implies that their rate of growth or accretion exceeds the rate of their degradation. As is well known, amyloid forms of proteins can be much more resistant to proteolysis than are their non-amyloid forms. Thus, one possibility is that many of these atherosclerotic proteins have morphed into amyloid forms. First, we summarise the extensive evidence for this, that is both observational (using various amyloid-structure-determining methods) and computational (using the program AmyloGram), showing that the amyloid(ogenic) potential of proteins found in plaques is significantly greater than that of most typical proteins. Thus, while 79% of human proteins have an AmyloGram score exceeding 0.7, with a median value of 0.81, typically more than 90% of proteins in plaques have AmyloGram scores exceeding 0.7, with a median score around 0.86. The probability-of-superiority values are around 0.615–0.627 against the human proteome. In addition, a Mann-Whitney test bootstrapped 20,000 times gave a 95% CI 0.0411–0.0497 for the difference in median AmyloGram score in Lewy bodies vs the human proteome. Secondly, while there is no significant relation between the overall hydropathy and amyloidogenic tendency of individual proteins, we recognise that amyloid forms of proteins expose many hydrophobic surface patches. These can act as scaffolds for other hydrophobic constituents of plaque. Overall the extensive new evidence provided here of an enrichment of amyloid forms of proteins in atherosclerotic and similar plaques can account, at least in part, for their resistance to proteolytic degradation. This has therapeutic implications.

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