Abstract P274: Inhibition Of Abnormal Exosome Release Prevents Excessive Aortic Stiffness And Relaxation Dysfunction In Diet-induced Obesity

Abstract

Interactions between over-nutrition and abnormal exosome release impact insulin sensitivity and the development of cardiovascular disease (CVD). Recent data have shown that exosomes can be released from various cell types, including adipocytes and vascular cells, and that they exist in body fluids and tissues functioning as mediators of cell-cell communication. However, the specific role of exosomes in diet-induced excessive vascular stiffness and hypertension has not been explored. Accordingly, we hypothesized that abnormal release of exosomes contributes to western diet (WD)- induced aortic stiffening and impaired vascular diastolic relaxation. We further posited that GW4869, an antagonist of neutral sphingomyelinase 2 (nSMase2) which promotes exosome production and release, would prevent WD-induced aortic stiffening and impaired vascular relaxation. Six week-old female C57BL/6L mice were fed a mouse chow (CD) or WD containing excess fat (46%) and fructose (17.5%) for 16 weeks with or without GW4849. To this point, 200 μl of 0.3 mg/mL GW4869 in 0.9% normal saline (60 μg/mouse; 2-2.5 μg/g body weight) was injected intraperitoneally every 48 hours for 12 weeks. 16 weeks of WD induced an increase of aortic stiffness as examined by pulse wave velocity (PWV) and impaired the aortic vasodilation responses to acetylcholine (Ach) and sodium nitroprusside (SNP) (10 -9 -10 -4 mol/L). However, GW4869 treatment prevented the WD-induced excessive aortic stiffness, as well as impairment of endothelium dependent/independent vascular relaxation. There were no significant differences in blood pressure between each group examined by tail cuff blood pressure measurement. These findings support the hypothesis that abnormal release of exosomes play an important role in WD-induced excessive aortic stiffness, impaired vascular relaxation and CVD in diet-induced obesity.