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In a groundbreaking study, investigators from Weill Cornell Medicine have identified a novel approach to harness the protective effects of sphingolipids, a type of fat-related molecule, in blood vessels, offering a promising new strategy for the treatment of coronary artery disease.
Published in Circulation Research on March 8, the study reveals that increasing levels of a sphingolipid known as S1P in artery-lining endothelial cells can effectively slow the development and progression of coronary artery disease in animal models. Dr. Onorina Laura Manzo, a postdoctoral researcher in the laboratory of Dr. Annarita Di Lorenzo, spearheaded the research as the lead author.
Sphingolipids, named after the enigmatic sphinx of ancient mythology, have long intrigued scientists due to their elusive biological functions. Recent studies have highlighted their relevance in coronary artery disease, with lower bloodstream levels of S1P observed in patients with this condition. However, the precise roles of these lipids have remained unclear until now.
Using an innovative mouse model developed by the research team, the study unveiled that stress-induced changes in arterial blood pressure trigger an increase in S1P production in endothelial cells as a protective response against coronary artery disease. Ordinarily, this response is temporary, but deleting a protein called NOGO-B, which inhibits S1P production, allows for sustained elevation of endothelial S1P levels, rendering the animals significantly more resistant to coronary artery disease and associated mortality.
A significant revelation from the study challenges the prevailing understanding of another group of sphingolipids called ceramides. While prior studies have linked high bloodstream levels of ceramides to coronary artery disease, the researchers found that levels of ceramides in artery-lining endothelial cells remained consistent regardless of disease status. This suggests that the role of ceramides in coronary artery disease warrants a reevaluation.
The implications of these findings are profound, laying the groundwork for the development of drugs that boost S1P levels to treat or prevent coronary artery disease. With coronary artery disease remaining the leading cause of mortality worldwide, affecting millions of individuals in the United States alone, novel therapeutic approaches are urgently needed.
The research was supported by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health, through grant numbers R01HL126913 and R01HL152195, as well as a Harold S. Geneen Charitable Trust Award for Coronary Heart Disease Research, underscoring the significance of the study’s implications for future treatments in cardiovascular medicine.
