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- W3168958129 abstract "Increased plasma ceramide levels and microvascular dysfunction are both independent risk factors for major adverse cardiac events (MACE). We have previously shown that chronic exposure to exogenous ceramide promotes microvascular endothelial dysfunction, defined as hydrogen peroxide (H2O2)-mediated flow-induced dilation (FID) as opposed to dilation due to formation and release of endothelial nitric oxide (NO). Interestingly, ceramide and its metabolites (e.g. sphingosine-1-phosphate; S1P) have also been shown to stimulate production of NO. Our previous studies indicate that activation of the ceramide-producing enzyme neutral sphingomyelinase (NSmase) in necessary for NO-mediated FID. We therefore hypothesized that formation of S1P is responsible for cellular increases in NO from both acute exogenous administration as well as endogenous formation of ceramide from shear. Human resistance arterioles (100-200µm) were dissected from adipose tissue collected from healthy patients and were prepared for videomicroscopy. Increasing doses of exogenous C2 ceramide (10-9 to 10-5 M) were administered in the absence or presence of the NO scavenger c-PTIO (1µM) and a sphingosine kinase inhibitor (SpKi, 5µM). We observed a dose-response increase in arteriolar dilation from ceramide (46.9%±10.3 of maximal dilator capacity±SEM, n=3) that was impaired by c-PTIO (15%±6.0, n=3). Ceramide-induced dilation was also decreased in the presence of the SpKi (20.8%±4.0, n=3). To examine the role of S1P formation in NO-mediated FID, SpKi was administered to healthy arterioles (5µM, 30 min) prior to initiating flow (pressure gradient 5-100cm H2O) and a dramatic decrease in overall dilation was observed (7.7%±8.0, n=3). Together these findings suggest that NO generated from ceramide is primarily due to the formation of S1P, a process also critical to maintain FID in arterioles from healthy individuals." @default.
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- W3168958129 date "2021-05-01" @default.
- W3168958129 modified "2023-10-16" @default.
- W3168958129 title "Investigation of the Dual Functional Role of Ceramide in the Human Microcirculation" @default.
- W3168958129 doi "https://doi.org/10.1096/fasebj.2021.35.s1.03010" @default.
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