Adiponectin Stimulates Production of Nitric Oxide in Vascular Endothelial Cells*

By Hui Chen, M. Montagnani, T. Funahashi, I. Shimomura, M. Quon. Journal of Biological Chemistry, 2003

1,027 citations recorded by the source corpus.

Adiponectin is secreted by adipose cells and mimics many metabolic actions of insulin. However, mechanisms by which adiponectin acts are poorly understood. The vascular action of insulin to stimulate endothelial production of nitric oxide (NO), leading to vasodilation and increased blood flow is an important component of insulin-stimulated whole body glucose utilization. Therefore, we hypothesized that adiponectin may also stimulate production of NO in endothelium. Bovine aortic endothelial cells in primary culture loaded with the NO-specific fluorescent dye 4,5-diaminofluorescein diacetate (DAF-2 DA) were treated with lysophosphatidic acid (LPA) (a calcium-releasing agonist) or adiponectin (10 μg/ml bacterially produced full-length adiponectin). LPA treatment increased production of NO by ∼4-fold. Interestingly, adiponectin treatment significantly increased production of NO by ∼3-fold. Preincubation of cells with wortmannin (phosphatidylinositol 3-kinase inhibitor) blocked only adiponectin- but not LPA-mediated production of NO. Using phospho-specific antibodies, we observed that either adiponectin or insulin treatment (but not LPA treatment) caused phosphorylation of both Akt at Ser473 and endothelial nitric-oxide synthase (eNOS) at Ser1179 that was inhibitable by wortmannin. We next transfected bovine aortic endothelial cells with dominant-inhibitory mutants of Akt (Akt-AAA) or AMP-activated protein kinase (AMPK) (AMPKK45R). Neither mutant affected production of NO in response to LPA treatment. Importantly, only AMPKK45R, but not Akt-AAA, caused a significant partial inhibition of NO production in response to adiponectin. Moreover, AMPK-K45R inhibited phosphorylation of eNOS at Ser1179 in response to adiponectin but not in response to insulin. We conclude that adiponectin has novel vascular actions to directly stimulate production of NO in endothelial cells using phosphatidylinositol 3-kinase-dependent pathways involving phosphorylation of eNOS at Ser1179 by AMPK. Thus, the effects of adiponectin to augment metabolic actions of insulin in vivo may be due, in part, to vasodilator actions of adiponectin.

Subfields: Endocrine and Autonomic Systems, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/a666be930c60dde5761b9c09ab70dc930481c828

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Citations in the corpus

Adiponectin: A novel adipokine linking adipocytes and vascular function. (2004, positive): “Consistent with this, concentrations of fAd similar to those found in the circulation have been shown to enhance NO production in cultured aortic endothelial cells (25, 40).”
Adiponectin Regulation and Function (2018, positive): “Many of the beneficial effects of adiponectin on the vasculature are mediated by its ability to increase eNOS expression/activity, resulting in increased NO production (32, 95) (Fig.”
Endothelial dysfunction and vascular disease – a 30th anniversary update (2017, background): “…of eNOS, increasing the bioavailability of both BH4 and NO, suppressing endothelial cell activation and apoptosis and promoting endothelial repair (Chen et al. 2003, Hattori et al. 2003, Tan et al. 2004, Cheng et al. 2007, Li et al. 2007b, Wang & Scherer 2008, Zhu et al. 2008, Margaritis et al.…”
Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease (2020, background): “Adiponectin also stimulates endothelial nitric oxide synthase (eNOS), which maintains healthy vascular tone (439, 440).”
Cardiovascular actions of insulin. (2007, background): “Similar to insulin, adiponectin has vasodilator actions to stimulate NO production in endothelial cells (320, 321).”