Heart Disease’s Jekyll and Hyde

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Depending on context, the molecule microRNA-146a can either promote or prevent fatty plaques.
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Overindulging in high-fat foods, alcohol, physical inactivity or smoking can significantly increase a person’s risk of developing heart disease.

Dr. Jekyll and Mr. Hyde are famous literary characters that behaved very differently: one was kind and sociable and the other evil and self-indulgent. Eventually, we learn that they are one and the same person.

TGHRI Scientist Dr. Jason Fish has demonstrated that, like Jekyll and Hyde, a molecule known as microRNA-146a (miR-146a) can play two different roles in heart disease, depending on the context. miR-146a is produced in many different types of cells throughout the body, including cells that comprise the immune and cardiovascular systems.

Heart disease is the leading cause of death worldwide. It is characterized by the accumulation of fatty deposits, known as plaques, in the blood vessels that supply the heart with oxygenated blood. Over a long period of time, these plaques can build-up until they completely block the vessels, preventing the heart from receiving enough blood to keep it pumping.

Although researchers do not fully understand the molecular mechanisms that trigger and promote plaque formation—a process known as atherosclerosis—they suspect that miR-146a could be involved. Previous clinical studies have detected high levels of miR-146a in atherosclerosis plaques. Moreover, modifications to the structure of the miR-146a molecule can alter a person’s risk of developing heart disease.

The recent study, led by Dr. Fish and his PhD student Henry Cheng, examined the effects of depleting miR-146a in different types of cells in an experimental model of atherosclerosis. The researchers found that when miR-146a is depleted from bone marrow, harmful plaque production was reduced; however, miR-146a’s absence also compromised the bone marrow’s activity.

Depleting miR-146a did not always reduce plaque formation. In fact, when depleted from the cells that line blood vessels miR-146a had the opposite effect: it promoted plaques.

These findings highlight the importance of cell context within biological systems: a molecule’s role in disease can depend on where it functions. Moreover, they reveal that augmenting levels of miR-146a in certain cells could represent a new strategy for preventing heart disease.

This work was supported by the Canadian Institutes of Health Research; the Heart & Stroke Foundation of Canada; the Canada Foundation for Innovation; the Ontario Ministry of Research, Innovation and Science; the Heart & Stroke Richard Lewar Centre of Excellence in Cardiovascular Research; the Canadian Vascular Network; and the Toronto General & Western Hospital Foundation. JE Fish holds a Tier 2 Canada Research Chair in in Vascular Cell and Molecular Biology.

Cheng HS, Besla R, Li A, Chen Z, Shikatani EA, Nazari-Jahantigh M, Hammoutène A, Nguyen MA, Geoffrion M, Cai L, Khyzha N, Li T, MacParland SA, Husain M, Cybulsky MI, Boulanger CM, Temel RE, Schober A, Rayner KJ, Robbins C, Fish JE. Paradoxical Suppression of Atherosclerosis in the Absence of microRNA-146a. Circ Res. 2017 Jun 21. doi: 10.1161/CIRCRESAHA.116.310529.