Membrane raft–lysosome redox signalling platforms in coronary endothelial dysfunction induced by adipokine visfatin
Open Access
- 7 September 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Cardiovascular Research
- Vol. 89 (2), 401-409
- https://doi.org/10.1093/cvr/cvq286
Abstract
The adipokine visfatin, produced during obesity, has been reported to participate in the development of cardiovascular disease associated with metabolic syndrome. The present study was designed to test a hypothesis that visfatin causes coronary endothelial dysfunction through lysosome trafficking and fusion to cell membranes, membrane raft (MR) clustering, and formation of redox signalosomes. By using confocal microscopy, it was found that visfatin, but not adiponectin, stimulated NADPH oxidase (NOX) subunits, gp91phox aggregation in MR clusters and p47phox translocation to these MR clusters in bovine coronary arterial endothelial cells (CAECs), leading to activation of NOX with a 2.5-fold increase in O2·− production. A signalling lipid, ceramide, was found to be enriched in such membrane MR–NOX complexes of CAECs. Lysosomal fluorescent dye (FM1-43) quenching and de-quenching revealed that visfatin induced the fusion of lysosomes to cell membranes and incorporation of acid sphingomyelinase and its product, ceramide, in such MR–NOX signalling platforms. Functionally, visfatin significantly attenuated endothelium-dependent vasodilation in small coronary arteries (by 80%), which was blocked by lysosomal function inhibitor and MR disruptors. These results suggest that lysosome-associated molecular trafficking and consequent ceramide accumulation in cell membrane may mediate the assembly of NOX subunits and their activation in response to adipokine visfatin in CAECs, thereby producing endothelial dysfunction in coronary circulation.This publication has 39 references indexed in Scilit:
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