Weill Cornell Medicine researchers have discovered a way to trigger the protective effects of a type of fat-related molecule known as sphingolipid in blood vessels, suggesting a promising new strategy for treating coronary artery disease.
In the study, published March 8 in Circulation investigation, researchers showed that increasing levels of a sphingolipid called S1P in the endothelial cells that line arteries slows the development and progression of coronary artery disease in an animal model. The lead author was Dr. Onorina Laura Manzo, a postdoctoral researcher in the laboratory of Dr. Annarita Di Lorenzo, associate professor of pathology and laboratory medicine at Weill Cornell Medicine.
Sphingolipids are named after the enigmatic sphinx of ancient mythology because their functions in biology have traditionally been somewhat mysterious. In recent years, there has been increasing evidence of its relevance in coronary artery disease; S1P levels in the bloodstream, for example, are lower in patients with this condition. But the precise functions of these lipids remain unclear.
In the new study, researchers sought a better understanding of those functions and the potential of sphingolipids as therapeutic targets. Despite the availability of cholesterol-lowering drugs and other interventions, coronary artery disease (the underlying cause of most heart attacks and many strokes) remains the world’s leading cause of mortality, affecting more than 20 million people in the United States alone. .
Using a new mouse model developed by the same group, the researchers found that blood pressure-related stress on the arteries, which will eventually induce coronary artery disease, triggers an increase in S1P production in endothelial cells, such as part of a protective response. This response is normally only temporary, but the removal of a protein called NOGO-B, which inhibits S1P production, allowed the increase in endothelial S1P production to be maintained, and made the animals much more resistant to the disease. of coronary arteries and associated mortality.
Another key finding is related to a different group of sphingolipids called ceramides. Previous studies have linked coronary artery disease to elevated levels of some ceramides in the bloodstream, and their causal role in the disease has been widely assumed. However, in their model, the researchers noted that while ceramide levels were high in the bloodstream, levels in the endothelial cells that line the arteries remained about the same regardless of coronary artery disease status. . This suggests that the current view on the role of ceramides in the disease should be revised.
Ultimately, the findings lay the groundwork for the development of drugs that boost S1P to treat or prevent coronary artery disease, the researchers concluded.
The work reported in this story was supported by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health, through grant numbers R01HL126913 and R01HL152195 and a Harold S. Geneen Charitable Trust Research Award of coronary heart diseases.