Clinical Research Studies

Atherosclerotic cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. Obesity increases risk for coronary heart disease and stroke. Prevention or regression of atherosclerosis would be informed by better understanding of the mechanisms that underlie development of atherosclerosis. Addressing this, we have identified a potential link between obese fat and atherosclerosis via exosomes. These exosomes, are capable of communicating between cells at a distance. The experiments proposed will define a mechanism by which obesity can lay the foundation for atherosclerosis and cardiovascular disease. Further, this will be useful in identifying obese patients at highest risk of developing cardiovascular disease, and thus may benefit the most from pharmaceutical or surgical intervention. One of the hallmarks of atherosclerosis is macrophage cholesterol efflux impairment which leads to intracellular accumulation of modified low-density lipoprotein (LDL) and subsequent formation of plaque forming lipid-rich foam cells. Macrophage cholesterol homeostasis is a delicate balance among influx, endogenous synthesis, esterification/hydrolysis and efflux. Even with this knowledge, it is unclear how obesity impairs cholesterol homeostasis. While the link between obesity and atherosclerosis is strong epidemiologically, large variations exist in individual responses to obesity. For example, some patients with high adiposity have normal cardiovascular health, while others with low adiposity have frank atherosclerosis. Exosomes are actively shed endocytic vesicles that transport lipids, sugars, nucleic acids, and proteins between cells at a distance. Exosomal function is largely determined by their microRNA content. MicroRNAs (miRNAs) are non-coding RNA (19–22 nucleotides) that post-transcriptionally regulate gene expression by base-pairing with the 3' untranslated region of complementary messenger RNA targets. The biological contexts that determine the exosomal microRNA-ome and their relationship to atherosclerosis remain to be clarified.