Abstract 16304: Manipulation of the Sphingolipid Rheostat Alters the Mediator of Flow-Induced Dilation in the Human Microcirculation
Flow-induced dilation (FID) maintains vascular homeostasis and is inversely related to future cardiovascular events. Our laboratory has recently discovered that ceramide, a bioactive signaling lipid elevated in patients with CAD, initiates a switch in the mediator of FID from NO to mitochondrial-derived H2O2, the same transition that occurs between health and disease. Intracellular levels of ceramide are tightly controlled by neutral ceramidases, enzymes that degrade ceramide to sphingosine, a pathologically less active sphingolipid. We tested the hypothesis that inhibition of neutral ceramidase will alter the sphingolipid rheostat and trigger the change in mediator of FID. Small adipose arterioles (100-200μm) from patients without CAD were prepared for videomicroscopy and constricted with endothelin-1. Changes in internal diameter to flow were recorded. L-NAME (100μM) did not affect FID in healthy arterioles pre-treated with the neutral ceramidase inhibitor, Ceranib-1 (10μM, 16-20hrs), (83.6%±4.1 of maximal dilator capacity, n=7) compared to vehicle-treated control (76.9%±5.0, n=10), however dilation was abolished in the presence of PEG-Catalase (500 Units) (1.9%±4.9, n=7, p<0.01, one-way ANOVA). Vehicle dilation was no different from Ceranib-1 alone (76.9%±5.0, n=10, versus, 83.4%±6.4, n=6, respectively). These data suggest that neutral ceramidase is critical in regulating the sphingolipid rheostat within the endothelium and its inhibition is sufficient to change the mediator of FID from NO to H2O2 in arterioles from patients without CAD. We conclude that neutral ceramidase is a key mechanistic component of the sphingolipid rheostat that can ultimately affect the dilator mechanism of FID. Manipulation of the ceramide pathway may lead to novel therapies that maintain or restore physiological mechanisms of perfusion in the human microcirculation.
Author Disclosures: J.K. Freed: None. J.C. Hockenberry: None. D.D. Gutterman: Consultant/Advisory Board; Modest; General Electric. Consultant/Advisory Board; Significant; Impulse Dynamics.
- © 2014 by American Heart Association, Inc.