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The Missing Link between Haematopoiesis and Atherosclerosis?

That high cholesterol levels correlate with hematopoietic stem cell proliferation is not new anymore. Several studies have already suggested that this is precisely what results in the increase of immune cells in the bloodstream in turn responsible for atherosclerotic plaque formation. How this happens however is less clear.

Insights into the molecular mechanisms underlying this association may now have been revealed by a study newly published in Science.

The simplicity of genetic manipulation in zebrafish allowed the scientists to engineer fishes deficient in a high density lipoprotein (HDL) protein responsible for transporting cholesterol in the bloodstream (the cholesterol efflux–mediating protein apolipoprotein A-I binding protein 2, Aibp2). Lack of Aibp2 impaired HSPC formation in early haematopoiesis, suggesting that cholesterol metabolism is implicated in HSCs emergence. Indeed they found that Aibp2 regulated the master transcription factor sterol regulatory element–binding protein 2 (Srebp2) responsible for cholesterol synthesis. Moreover both proteins were found to regulate the Notch-signalling pathway intimately implicated in the specification of haematopoietic stem cells. The results correlated with higher circulating LDL, increased HSCs and upregulated SREBP2 and Notch pathway in persons with hypercholesterolemia.

IPEK scientists Esther Lutgens and Menno P.J. de Winther, who had the privilege to comment on this important piece of research in the New England Journal of Medicine, wrote: “The most notable aspect of the study is the implication of “cholesterol metabolism” genes in the biologic makeup of HSPCs. These findings provide support for the hypothesis that cholesterol metabolism is a driver of inflammation in cardiovascular disease.”

The hypothesis that cholesterol metabolism and haematopoiesis pathways are intrinsically linked is a fascinating emerging avenue of research which may pave the way to identifying new therapeutic targets for atherosclerosis therapies.

Science 2019

NEJM 2019