HIV antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir use different pathways to affect inflammation, senescence and insulin sensitivity in human coronary endothelial cells


Autoři: Martine Auclair aff001;  Anne-Claire Guénantin aff001;  Soraya Fellahi aff001;  Marie Garcia aff001;  Jacqueline Capeau aff001
Působiště autorů: Sorbonne Université, Paris, France aff001;  Inserm UMR_S938, Centre de Recherche Saint-Antoine, Paris, France aff002;  ICAN, Institute of Cardiometabolism and Nutrition, Paris, France aff003;  Department of Biochemistry, Tenon Hospital, APHP, Paris, France aff004
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226924

Souhrn

Objectives

Aging HIV-infected antiretroviral-treatment (ART)-controlled patients often present cardiovascular and metabolic comorbidities. Thus, it is mandatory that life-long used ART has no cardiometabolic toxicity. Protease inhibitors have been associated with cardiometabolic risk, integrase-strand-transfer-inhibitors (INSTI) with weight gain and the CCR5 inhibitor maraviroc with improved vascular function. We have previously reported that the INSTI dolutegravir and maraviroc improved, and ritonavir-boosted atazanavir(atazanavir/r) worsened, inflammation and senescence in human coronary artery endothelial cells (HCAEC)s from adult controls. Here, we analyzed the pathways involved in the drugs’ effects on inflammation, senescence and also insulin resistance.

Methods

We analyzed the involvement of the anti-inflammatory SIRT-1 pathway in HCAECs. Then, we performed a transcriptomic analysis of the effect of dolutegravir, maraviroc and atazanavir/r and used siRNA-silencing to address ubiquitin-specific-peptidase-18 (USP18) involvement into ART effects.

Results

Dolutegravir reduced inflammation by decreasing NFκB activation and IL-6/IL-8/sICAM-1/sVCAM-1 secretion, as did maraviroc with a milder effect. However, when SIRT-1 was inhibited by splitomicin, the drugs anti-inflammatory effects were maintained, indicating that they were SIRT-1-independant.

From the transcriptomic analysis we selected USP18, previously shown to decrease inflammation and insulin-resistance. USP18-silencing enhanced basal inflammation and senescence. Maraviroc still inhibited NFκB activation, cytokine/adhesion molecules secretion and senescence but the effects of dolutegravir and atazanavir/r were lost, suggesting that they involved USP18. Otherwise, in HCAECs, dolutegravir improved and atazanavir/r worsened insulin resistance while maraviroc had no effect. In USP18-silenced cells, basal insulin resistance was increased, but dolutegravir and atazanavir/r kept their effect on insulin sensitivity, indicating that USP18 was dispensable.

Conclusion

USP18 reduced basal inflammation, senescence and insulin resistance in coronary endothelial cells. Dolutegravir and atazanavir/r, but not maraviroc, exerted opposite effects on inflammation and senescence that involved USP18. Otherwise, dolutegravir improved and atazanavir/r worsened insulin resistance independently of USP18. Thus, in endothelial cells, dolutegravir and atazanavir/r oppositely affected pathways leading to inflammation, senescence and insulin resistance.

Klíčová slova:

Antiretrovirals – Endothelial cells – Inflammation – Insulin – Insulin resistance – Insulin signaling – Secretion – Tubulins


Zdroje

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