Grant: CIHR-ICRH Travel Awards - General pool

Background: Every 10 minutes a Canadian suffers a stroke. Most strokes are caused by the build-up of dangerous fatty deposits, called plaques, in the carotid arteries of the neck that supply blood to the brain. When plaques become unstable, pieces can break off and travel to the brain, where they can cut off blood flow and cause strokes. It is important to find out early when a plaque becomes unstable so it can be better treated and prevent strokes from happening. A key immune cell, called a macrophage, is highly present in plaques, and can transform into various phenotypes based on its environment. In unstable plaques, macrophages tend to exacerbate pro-inflammatory responses, whereas in stable plaques, macrophages attempt to resolve the inflammation. Moreover, an abundant circulating hormone called adiponectin, which plays a beneficial role in diabetes, obesity, and heart disease, may also play a key role in determining whether a plaque remains stable or becomes unstable. Adiponectin works like a key that must attach to its lock (receptors) to work beneficially. To this end, we investigated adiponectin’s role on macrophage phenotypes by determining whether defects in adiponectin receptors can cause plaques to become unstable. Methods: Using advanced laboratory methods, we examined how the absence of adiponectin receptors can affect macrophage phenotypes in response to adiponectin by measuring the inflammatory profiles. Results: Despite treatment with adiponectin, the loss of adiponectin receptor 2 resulted in an elevated pro-inflammatory profile compared to the loss of adiponectin receptor 1. Conclusions: Through this work, we demonstrated that downregulation of adiponectin receptor 2 compromised adiponectin’s anti-inflammatory actions by stimulating a pro-inflammatory profile. These findings help explain the environment of an unstable plaque, which seems to have decreased adiponectin receptor 2 expression coupled with increased inflammation. This study could help elucidate why certain plaques are dangerous, while others remain safe. A better understanding of the role of adiponectin and its receptors in plaques could establish them as important predictive tools in assessing stroke risk, as well as potential therapeutic targets.