Abstract P3126: Sphingomyelinase Participates Diet - Induced Increases In Aortic Stiffness And Cardiac Dysfunction

Excessive accumulation of ceramides induces mitochondria dysfunction and promotes toxicity in multiple types of cells, including endothelial cells and cardiomyocytes. Neutral sphingomyelinase (nSMase) is thought to increase ceramide levels through sphingomyelin hydrolysis, and the resultant increase in ceramides plays a role in the pathogenesis of a number of disorders, such as atherosclerosis and heart failure. While inhibition of nSMase attenuates the progression of atherosclerosis and heart failure, little is known regarding its role in correcting impaired metabolic signaling, arterial dysfunction and metabolic cardiomyopathy. Accordingly, we hypothesized that nSMase inhibition with GW4869, attenuates Western diet (WD) - induced increases in aortic stiffness and cardiac dysfunction through effects on pathways which lead to oxidative stress and inflammation. Six week-old female C57BL/6L mice were fed either a WD containing excess fat (46%) and fructose (17.5%) for 16 weeks or a standard chow diet (CD). Mice were treated with GW4869 (2.0 μg/g body weight, intraperitoneal injection every 48 hours for 12 weeks). WD consumption increased plasma nSMase activation and tissue nSMase2 expression in concert with aortic stiffening and impaired vasorelaxation as determined by pulse wave velocity (PWV) and wire myography, respectively. WD fed mice exhibited reduced EF (systolic dysfunction) and increased E/E’ and IVRT (diastolic dysfunction) determined by in vivo Doppler ultrasound. Moreover, these functional abnormalities were associated with attenuated AMP-activated protein kinase, Sirtuin 1, and endothelial nitric oxide synthase activation. These functional and metabolic abnormalities were blunted by in vivo GW4869 treatment. These findings indicate that targeting nSMase prevents diet - induced aortic stiffening and cardiac dysfunction by correction of impaired metabolic signaling.