Effect of the anti-retroviral drugs efavirenz, tenofovir and entricitabine on endothelial cell function: role of PARP

Mary Faltz, Hild Bergin, Elly Pilavachi, Guy Grimwade, Jon Mabley

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Highly active anti-retroviral therapy has proved successful in reducing morbidity and mortality associated with HIV infection though it has been linked to increased risk of cardiovascular disease. To date, the direct effects of the anti-retroviral drugs Efavirenz, Tenofovir and Emtricitabine on the vasculature relaxant response have not been elucidated, which impaired may predispose individuals to cardiovascular disease. Increased cellular oxidative stress and overactivation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) have been identified as central mediators of vascular dysfunction. The aim of this study was to investigate whether exposure to Efavirenz, Tenofovir or Emtricitabine directly causes endothelial cell dysfunction via overactivation of PARP. Exposure of ex vivo male rat aortic rings or in vitro endothelial cells to Efavirenz but not Tenofovir or Emtricitabine impaired the acetylcholine-mediated relaxant response, increased cellular oxidative stress and PARP activity, decreased cell viability and increased apoptosis and necrosis. Pharmacological inhibition of PARP protected against the Efavirenz-mediated impairment of vascular relaxation and endothelial cell dysfunction. Oestrogen exposure also protected against the Efavirenz-mediated inhibition of the vascular relaxant response, cell dysfunction and increased PARP activation. In conclusion, Efavirenz directly impairs endothelial cell function, which may account for the increased risk of developing cardiovascular complications with anti-retroviral therapy.
Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalCardiovascular Toxicology
DOIs
Publication statusPublished - 3 Jan 2017

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Tenofovir
efavirenz
Poly(ADP-ribose) Polymerases
Endothelial Cells
Pharmaceutical Preparations
Blood Vessels
Oxidative Stress
Cardiovascular Diseases
DNA Repair Enzymes
Acetylcholine
HIV Infections
Cell Survival
Estrogens
Necrosis
Pharmacology

Bibliographical note

The final publication is available at Springer via http://dx.doi.org/10.1007/s12012-016-9397-4

Keywords

  • Efavirenz
  • Emtricibine
  • Tenofovir
  • PARP
  • cardiovascular
  • endothelial
  • Oestrogen

Cite this

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abstract = "Highly active anti-retroviral therapy has proved successful in reducing morbidity and mortality associated with HIV infection though it has been linked to increased risk of cardiovascular disease. To date, the direct effects of the anti-retroviral drugs Efavirenz, Tenofovir and Emtricitabine on the vasculature relaxant response have not been elucidated, which impaired may predispose individuals to cardiovascular disease. Increased cellular oxidative stress and overactivation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) have been identified as central mediators of vascular dysfunction. The aim of this study was to investigate whether exposure to Efavirenz, Tenofovir or Emtricitabine directly causes endothelial cell dysfunction via overactivation of PARP. Exposure of ex vivo male rat aortic rings or in vitro endothelial cells to Efavirenz but not Tenofovir or Emtricitabine impaired the acetylcholine-mediated relaxant response, increased cellular oxidative stress and PARP activity, decreased cell viability and increased apoptosis and necrosis. Pharmacological inhibition of PARP protected against the Efavirenz-mediated impairment of vascular relaxation and endothelial cell dysfunction. Oestrogen exposure also protected against the Efavirenz-mediated inhibition of the vascular relaxant response, cell dysfunction and increased PARP activation. In conclusion, Efavirenz directly impairs endothelial cell function, which may account for the increased risk of developing cardiovascular complications with anti-retroviral therapy.",
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Effect of the anti-retroviral drugs efavirenz, tenofovir and entricitabine on endothelial cell function: role of PARP. / Faltz, Mary; Bergin, Hild; Pilavachi, Elly; Grimwade, Guy; Mabley, Jon.

In: Cardiovascular Toxicology, 03.01.2017, p. 1-12.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Bergin, Hild

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AU - Grimwade, Guy

AU - Mabley, Jon

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