N-Octanoyl Dopamine Inhibits the Expression of a Subset of κB Regulated Genes: Potential Role of p65 Ser276 Phosphorylation

Abstract

Background and PurposeCatechol containing compounds have anti-inflammatory properties, yet for catecholamines these properties are modest. Since we have previously demonstrated that the synthetic dopamine derivative N-octanoyl dopamine (NOD) has superior anti-inflammatory properties compared to dopamine, we tested NOD in more detail and sought to elucidate the molecular entities and underlying mechanism by which NOD down-regulates inflammation.Experimental ApproachGenome wide gene expression profiling of human umbilical vein endothelial cells (HUVECs) was performed after stimulation with TNF-α or in the combination with NOD. Confirmation of these differences, NFκB activation and the molecular entities that were required for the anti-inflammatory properties were assessed in subsequent experiments.Key ResultsDown regulation of inflammatory genes by NOD occurred predominantly for κB regulated genes, however not all κB regulated genes were affected. These findings were explained by inhibition of RelA phosphorylation at Ser276. Leukocyte adherence to TNF-α stimulated HUVECs was inhibited by NOD and was reflected by a diminished expression of adhesion molecules on HUVECs. NOD induced HO-1 expression, but this was not required for inhibition of NFκB. The anti-inflammatory effect of NOD seems to involve the redox active catechol structure, although the redox active para-dihydroxy benzene containing compounds also displayed anti-inflammatory effects, provided that they were sufficiently hydrophobic.Conclusions and ImplicationsThe present study highlighted important mechanisms and molecular entities by which dihydroxy benzene compounds exert their potential anti-inflammatory action. Since NOD does not have hemodynamic properties, NOD seems to be a promising candidate drug for the treatment of inflammatory diseases.

N-acyl dopamine derivates as lead compound for implementation in transplantation medicine

“…Because of their redox active catechol structure NADD have the propensity to inhibit the activation of redox dependent proinflammatory transcription factors, e.g. NF-κB, AP-1 and NFAT [64,65], and therefore they largely inhibit the expression of inflammatory mediators produced by endothelial cells [66] and proliferation of T cells [64][65][66][67].…”

Dopamine and Lipophilic Derivates Protect Cardiomyocytes against Cold Preservation Injury

“…Yet it suggests that if such a target exists, the redox activity and hydrophobicity of the protective compound seem to have a strong influence on the activity of this target. NOD, BBNB, and BBNO all have the propensity to inhibit nuclear factor kB upon stimulation with tumor necrosis factor a (Hottenrott et al, 2013). Therefore, even though NOD, BBNB, and BBNO are distinct in their chemical structure, their common chemical characteristics, that is, redox activity and hydrophobicity, appear to be sufficient to inhibit the same cellular target.…”

N-octanoyl Dopamine Attenuates the Development of Transplant Vasculopathy in Rat Aortic Allografts Via Smooth Muscle Cell Protective Mechanisms

“…We previously described a strong anti-inflammatory effect of NOD on endothelial cells 33 and T cells. 34 These observations were not confirmed in the current study because NOD did not influence the degree of infiltrated macrophages, T cells, and NK cells in vivo.…”

“…Inasmuch as in vitro studies have indicated that NOD inhibits the expression of endothelial cell adhesion molecules, leukocyte adhesion to the endothelium, 33 and T cell activation, 34 the present study was conducted to assess if NOD has therapeutic efficacy to reduce TV in a model of allogeneic aorta transplantation in rats. The following 2 major findings were obtained in this study.…”

“…30 Because low-dose donor dopamine treatment resulted in hypertension and/or tachycardia in approximately 12.5% of the cases, 28 we have conjugated the amine side chain of dopamine with n-octanoic acid, which likely impairs adrenergic and dopaminergic receptor engagement and results in a far more protective compound. 31 N-octanoyl dopamine (NOD) not only protects cells and tissues against prolonged hypothermic preservation, 31 it also strongly inhibits platelet function ex vivo, 32 prevents NF-κB activation in vitro 33 and inhibits T cell activation and proliferation. 34 In vivo, we showed that NOD also mitigates ischemia-induced acute kidney injury.…”