MONTREAL, February 3, 2021 – A Canadian research team headed by Professor Alexey Pshezhetsky of CHU Sainte-Justine has discovered a new pathogenic pathway that leads to atherosclerosis, also known as "hardening of the arteries." This work has led to the identification of new potential therapeutic targets, bringing hope to those struggling with this serious disease. The results of the study are presented in the Journal of American Heart Association.

The team investigated the role of neuraminidase enzymes in the development of atherosclerosis. These enzymes, which regulate metabolic processes, are believed to play a key role in the removal of sialic acid fragments present in LDL (low density lipoprotein) cholesterol, or "bad cholesterol." Without sialic acid, cholesterol would accumulate in an uncontrolled manner.

Primary cause of death worldwide

Atherosclerosis is the main cause of death and disability in developed countries. It is a chronic inflammatory disease affecting medium-sized and large arteries and is characterized by the development of atheromatous plaques.

Atheromatous plaques form when there is an excess of bad cholesterol clogging up our "plumbing." Over time, these deposits gradually become saturated with blood products and calcium, which harden and impede circulation. 

The therapeutic management of atherosclerosis involves lowering bad cholesterol levels with the help of statins, hydroxymethylglutaryl-CoA reductase inhibitors, which decrease the likelihood of atherosclerotic events. Unfortunately, only about 35% of patients benefit from this drug.

Promising new avenue of treatment

Previous studies have shown that a large number of risk factors contribute to this condition, including smoking, hypertension, genetic predisposition, age, gender and obesity. However, the cellular, biochemical and molecular mechanisms underlying the development of atheromatous plaques remain poorly understood.

"Based on the hypothesis that neuraminidase enzymes play a role in the disease, we demonstrated through preclinical models that genetic inactivation or pharmacological inhibition of neuraminidases 1 and 3 (NEU1 and NEU3) significantly delay the formation of aortic fatty streaks," says Alexey Pshezhetsky, researcher at CHU Sainte Justine and full professor at Université de Montréal.

"Why? Because neuraminidase removes sialic acids from bad cholesterol, which increases its uptake by white blood cells in the arteries." 

Atherosclerosis occurs when the affected arterial wall reacts by sending chemical signals that cause certain types of leukocytes to migrate into the subendothelial space, where they attach and differentiate into residential macrophages. These macrophages then recognize and absorb bad cholesterol that seeps into the subendothelial space of the arterial wall. This leads to the uncontrolled uptake of cholesterol, which then converts to foam cells (cells bloated with fat droplets). This in turn triggers a cascade of immune responses leading collectively to the formation of atheromatous plaques, creating a potentially dangerous reduction in blood flow.

What are the clinical implications?

Considering that atherosclerosis is currently the most common cause of heart attacks, strokes and vascular disease in developed countries, the potential of this discovery for population health is enormous.

"Our study suggests that specific inhibitors of NEU1 and NEU3 or of biological substances targeting these enzymes may become promising potential drug targets to provide a preventive or therapeutic effect in atherosclerosis," says Professor Christopher W. Cairo of the University of Alberta, who has helped generate small molecules of neuraminidase inhibitors in the laboratory.

Optimal dosage and duration of the drugs will need to be carefully evaluated in future preclinical work, as will the safety and efficacy of this therapeutic approach, which has yet to be demonstrated in humans.

About the study

The article "Neuraminidases 1 and 3 trigger atherosclerosis by desialylating low-density lipoproteins and increasing their uptake by macrophages" was published in February 2021 in the Journal of American Heart Association. The co-first authors are Ekaterina P. Demina, PhD, and Viktorija Smutova, PhD, under the supervision of Alexey V. Pshezhetsky. The lead author is Alexey V. Pshezhetsky, researcher, Director of the Elisa Linton Sanfilippo Research Laboratory; Scientific Supervisor, Biochemical Genetics Laboratory, CHU Sainte-Justine, Full Professor, Department of Pediatrics, Université de Montréal.

Alexey V. Pshezhetsky and Christopher W. Cairo are both investigators with the Canadian Glycomics Network (GlycoNet), a Canada-wide network of researchers that are working further our understanding of the biological roles of sugars.

The study was funded by GlycoNet, the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC), a Canada Research Chair and the Russian Science Foundation.

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