In:
Endocrinology, The Endocrine Society, Vol. 150, No. 8 ( 2009-08-01), p. 3584-3593
Abstract:
The AMP-activated protein kinase (AMPK) lies upstream of Akt in the pathway leading to endothelial NO synthase (eNOS) activation. Whether leptin promotes eNOS activation via AMPK-dependent activation of Akt, and which of the two AMPKα catalytic subunits is involved, remains unknown. Leptin resistance may be partly attributed to interaction between leptin and C-reactive protein (CRP). We hypothesized that leptin effect on eNOS activation in human aortic endothelial cells might be blunted by direct interaction with human recombinant CRP. Small interfering RNAs (siRNAs) were used to knock down expression of α1- or α2-AMPK in transient transfection assay to evaluate which is involved in this pathway and whether leptin effect on eNOS activation in human aortic endothelial cells might be blunted by direct interaction with human CRP. siRNA-mediated down-regulation of AMPKα1, but not AMPKα2, abolished leptin-induced Akt-Ser473 phosphorylation, eNOS-Ser1177 phosphorylation, eNOS activation, and cGMP accumulation. By contrast, siRNA-mediated knockdown of Akt1 did not affect AMPKα1 phosphorylation, but it abolished leptin-induced phosphorylation of Akt-Ser473 and eNOS-Ser1177, suggesting that Akt functions downstream of AMPKα1. Preincubation of leptin with human recombinant CRP impaired leptin-induced AMPK activation, eNOS-Ser1177 phosphorylation, eNOS activity, and intracellular cGMP accumulation. The data are consistent with a model implicating an AMPKα1→Akt→eNOS pathway leading to NO production in response to leptin supporting the idea that interaction between leptin and CRP may have a role in impairing leptin effect on eNOS activation, suggesting a link between leptin resistance, low-grade inflammation, and endothelial dysfunction.
Type of Medium:
Online Resource
ISSN:
0013-7227
,
1945-7170
DOI:
10.1210/en.2008-0921
Language:
English
Publisher:
The Endocrine Society
Publication Date:
2009
detail.hit.zdb_id:
2011695-0
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