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The effect of type 1 IFN on human aortic endothelial cell function in vitro: relevance to systemic lupus erythematosus.

ABSTRACT: Cardiovascular disease (CVD) is an important cause of morbidity and mortality in patients with systemic lupus erythematosus. The etiopathogenesis of premature CVD is not fully understood, but recently interferon-alpha (IFN?) has been implicated as a contributing factor. Since IFN? has been associated with both disease activity and endothelial dysfunction in lupus patients, we aimed to determine whether IFN? has direct effects on human aortic endothelial cell (HAoEC) function in vitro. We studied the function of IFN?2b-treated HAoECs in terms of cell proliferation, capillary-like network formation, and nitric oxide (NO) generation. Changes in gene expression were also analyzed using an exon gene array. IFN?2b regulated the expression of 198 genes, including recognized interferon-stimulated genes (ISGs). Gene ontology analysis showed over-representation of genes involved in antigen presentation and host response to virus but no significant changes in clusters of genes recognized as important in endothelial cell activation or dysfunction. HAoEC proliferation, tubule formation, and NO bioavailability were unchanged, suggesting that IFN? in isolation does not have a direct impact on aortic endothelial cell function.

SUBMITTER: Reynolds JA

PROVIDER: S-EPMC4015474 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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The effect of type 1 IFN on human aortic endothelial cell function in vitro: relevance to systemic lupus erythematosus.

Reynolds John A JA Ray David W DW Zeef Leo A H LA O'Neill Terence T Bruce Ian N IN Alexander M Yvonne MY

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20140120 5

Cardiovascular disease (CVD) is an important cause of morbidity and mortality in patients with systemic lupus erythematosus. The etiopathogenesis of premature CVD is not fully understood, but recently interferon-alpha (IFNα) has been implicated as a contributing factor. Since IFNα has been associated with both disease activity and endothelial dysfunction in lupus patients, we aimed to determine whether IFNα has direct effects on human aortic endothelial cell (HAoEC) function in vitro. We studied ...[more]

PMID: 24444308

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Project description:IntroductionEndothelial function is significantly impaired in patients with SLE compared to healthy controls. Elevated activation of the mammalian target of rapamycin complex 1 (mTORC1) is reported in humans and mice with SLE. However, it is unclear if elevated mTORC1 in SLE contributes to impaired mitophagy and endothelial dysfunction. Therefore, we tested the hypothesis that inhibiting mTORC1 with rapamycin would increase mitophagy and attenuate endothelial dysfunction and inflammatory responses in SLE.MethodsNine-week-old female lupus-prone (MRL/lpr) and healthy control (MRL/MpJ) mice were randomly assigned into rapamycin treatment (lpr_Rapamycin and MpJ_Rapamycin) or control (lpr_Control and MpJ_Control) groups. Rapamycin was injected i.p. 3 days per week for 8 weeks. After 8 weeks, endothelium-dependent vasorelaxation to acetylcholine (ACh) and endothelium-independent vasorelaxation to sodium nitroprusside (SNP) were measured in thoracic aortas using a wire myograph.ResultsMTORC1 activity was increased in aorta from lpr mice as demonstrated by increased phosphorylation of s6rp and p70s6k and significantly inhibited by rapamycin (s6rp, p < 0.0001, p70s6k, p = 0.04, respectively). Maximal responses to Ach were significantly impaired in lpr_Control (51.7% ± 6.6%) compared to MpJ_Control (86.7% ± 3.6%) (p < 0.0001). Rapamycin prevented endothelial dysfunction in the thoracic aorta from lupus mice (lpr_Rapamycin) (79.6% ± 4.2%) compared to lpr_Control (p = 0.002). Maximal responses to SNP were not different across groups. Phosphorylation of endothelial nitric oxide synthase also was 42% lower in lpr_Control than MpJ_Control and 46% higher in lpr_Rapamycin than lpr_Control. The inflammatory marker, vascular cell adhesion protein 1 (Vcam 1), was elevated in aorta from lupus mice compared with healthy mice (p = 0.001), and significantly reduced with Rapamycin treatment (p = 0.0021). Mitophagy markers were higher in lupus mice and reduced by rapamycin treatment, suggesting altered mitophagy in lpr mice.ConclusionCollectively, these results demonstrate the beneficial effects of inhibiting mTORC1 on endothelial function in SLE mice and suggest inflammation and altered mitophagy contribute to endothelial dysfunction in SLE.

Dataset Information

The effect of type 1 IFN on human aortic endothelial cell function in vitro: relevance to systemic lupus erythematosus.

Publications

The effect of type 1 IFN on human aortic endothelial cell function in vitro: relevance to systemic lupus erythematosus.

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