Hypertension in relation to nitric oxide, asymmetric dimethylarginine, and inflammation: different patterns in heart transplant recipients and individuals with essential hypertension

Holm, Torbjörn; Aukrust, Pål; Aagaard, Erik; Ueland, Thor; Haugstad, Tor S.; Kjekshus, John; Simonsen, Svein; Frøland, Stig S.; Gullestad, Lars; Andreassen, Arne K.

doi:10.1097/00007890-200211270-00009

Cited by 12 publications

(9 citation statements)

References 33 publications

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“…In the present study, the results showed that ADMA induced the secretion of inflammatory cytokines TNF-and sICAM-1 in cultured endothelial cells. Clinical studies showed that the levels of ADMA and the concentrations of CRP and TNF-were strongly interrelated (Holm et al 2002;Zoccali et al 2002;Nanayakkara et al 2005). These findings suggest that ADMA, in addition to inhibiting NOS, may also participate in the inflammation processes of endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 98%

The inhibitory effect of simvastatin on the ADMA-induced inflammatory reaction is mediated by MAPK pathways in endothelial cells

Jiang

Wang

et al. 2007

Biochem. Cell Biol.

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Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is emerging as a key contributor for endothelial dysfunction associated with inflammation. Statins can inhibit vascular inflammatory reaction and improve endothelial function. The aim of this study was to investigate in human endothelial cells the signaling pathways of ADMA-induced inflammatory reaction and potential inhibitory effects of simvastatin. Endothelial cells were cultured and used for all of the studies. Tumor necrosis factor-alpha(TNF-alpha) and soluble intercellular adhesion molecule-1 (sICAM-1) were determined by enzyme-linked immunosorbent assay. Nuclear factor-kappaB (NF-kappaB) was assayed by electrophoretic mobility shift assay. The activation of mitogen-activated protein kinases (MAPKs), including p38 MAPK and extracellular signal-related kinase (ERK(1/2)), were characterized by Western blot analysis. Treatment with ADMA (3-30 micromol/L) increased the concentration of sICAM-1 in a dose-dependent manner. ADMA (30 micromol/L) significantly enhanced the concentrations of TNF-alpha and sICAM-1, the activity of NF-kappaB and the phosphorylation of p38 MAPK and ERK(1/2). The increased secretion of TNF-alpha and sICAM-1 and the increased activity of NF-kappaB by ADMA were altered by SB203580 (5 micromol/L) or PD98059 (20 micromol/L), but not by LY294002 (20 micromol/L). Simvastatin (0.1, 0.5, or 2.5 micromol/L) markedly inhibited the elevated concentrations of TNF-alpha and sICAM-1, the activity of NF-kappaB, and the phosphorylation of p38 MAPK and ERK(1/2) induced by ADMA. Simvastatin inhibited ADMA-induced inflammatory reaction by p38 MAPK and ERK(1/2) pathways in cultured endothelial cells.

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Section: Discussionmentioning

confidence: 98%

The inhibitory effect of simvastatin on the ADMA-induced inflammatory reaction is mediated by MAPK pathways in endothelial cells

Jiang

Wang

et al. 2007

Biochem. Cell Biol.

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“…In this study, ADMA, a NO synthase inhibitor, was found to be significantly higher in DS patients with PH than in those DS patients without PH. Elevated levels of ADMA have been shown in adult studies to be associated with not only systemic hypertension [12,18] but also PH [14,27]. Levels of ADMA have also been shown to predict morbidity and mortality in various cardiovascular disease states [14,17].…”

Section: Discussionmentioning

confidence: 99%

Down syndrome patients with pulmonary hypertension have elevated plasma levels of asymmetric dimethylarginine

et al. 2010

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Down syndrome (DS) patients have an increased risk of developing pulmonary hypertension (PH). Increased plasma levels of asymmetric dimethylarginine (ADMA) may contribute to vascular dysfunction in adults with idiopathic pulmonary hypertension. Our goal was to test the hypothesis that DS patients with PH have higher plasma levels of ADMA than DS patients without PH. DS patients with definitive PH (n = 6) and DS patients with no evidence of PH (n = 12) were studied. Plasma levels of arginine, ADMA, and nitrite/nitrate (NOx; stable metabolites of nitric oxide (NO)) were measured. Plasma arginine concentration was lower (p < 0.05) in PH patients (23 ± 11 μM) versus non-PH patients (46 ± 24 μM). Plasma ADMA concentration was higher (p < 0.005) in PH patients (18.0 ± 4.2 μM) versus non-PH patients (8.6 ± 5.9 μM). Plasma NOx was lower (p < 0.05) in PH patients (4.5 ± 1.7 μM) versus non-PH patients (8.5 ± 7.3 μM). These results are consistent with ADMA contributing to lower NO production in DS patients with PH and suggest that ADMA levels may be a potential biomarker for PH in DS patients.

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“…Others have demonstrated that, under physiological conditions, the production of EDHF can be reduced by over production of NO (Bauersachs et al 1996; McCulloch et al 1997). It may be relevant that up‐regulation of nitric oxide synthesis occurs with the inflammatory response (Holm et al 2002), a feature of the metabolic syndrome (Bonora et al 2003). The observation of an increased NO‐mediated component of relaxation in the femoral arteries of the male offspring of fat‐ded dams would lend some support to this suggestion.…”

Section: Discussionmentioning

confidence: 99%

Impaired EDHF‐mediated vasodilatation in adult offspring of rats exposed to a fat‐rich diet in pregnancy

Taylor

Khan

Hanson

et al. 2004

The Journal of Physiology

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We recently reported vascular dysfunction in adult offspring of rats fed a fat-rich (animal lard) diet in pregnancy. This study reports further characterization of constrictor and dilator function in mesenteric and caudal femoral arteries from 180-day-old offspring of dams fed the high fat diet (OHF). Endothelium-dependent relaxation in response to acetylcholine (10 −9 -10 −5 M) was impaired in mesenteric small arteries from male and female OHF compared with offspring of dams fed normal chow (males (maximum percentage relaxation): OHF 67.92 ± 2.89, n = 8 versus control 92.08 ± 2.19, n = 8, P < 0.01). Substantial relaxation in response to acetycholine in control mesenteric arteries remained after inhibition of nitric oxide synthase, soluble guanylate cyclase and cyclo-oxygenase but was blocked by 25 mM potassium. This component of relaxation, attributed to EDHF, was significantly reduced in OHF mesenteric arteries compared with controls. However, EDHF played a minor role in acetylcholine-induced relaxation in both control and OHF femoral caudal arteries (male and female). In these arteries, in contrast to mesenteric vessels, acetylcholine-induced relaxation was significantly enhanced in OHF but only in males (ACh (maximum percentage relaxation): OHF 58.40 ± 4.39, n = 8 versus male controls 32.18 ± 6.36, P < 0.05). This was attributable to enhanced nitric oxide-mediated relaxation. In conclusion, reduced endothelium-dependent relaxation in OHF mesenteric arteries is due to impaired EDHF-mediated relaxation. This defect was not apparent in femoral arteries in which EDHF has a less prominent role.

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Hypertension in relation to nitric oxide, asymmetric dimethylarginine, and inflammation: different patterns in heart transplant recipients and individuals with essential hypertension

Abstract: Our findings suggest that different mechanisms may be operating in the pathogenesis of posttransplant compared with essential hypertension, with persistent inflammation, raised NO2(-) + NO3(-), and decreased ADMA levels characterizing the former group.

Cited by 12 publications

References 33 publications

The inhibitory effect of simvastatin on the ADMA-induced inflammatory reaction is mediated by MAPK pathways in endothelial cells

The inhibitory effect of simvastatin on the ADMA-induced inflammatory reaction is mediated by MAPK pathways in endothelial cells

Down syndrome patients with pulmonary hypertension have elevated plasma levels of asymmetric dimethylarginine

Impaired EDHF‐mediated vasodilatation in adult offspring of rats exposed to a fat‐rich diet in pregnancy

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