title: Effect of the Anti-retroviral Drugs Efavirenz, Tenofovir and Emtricitabine on Endothelial Cell Function: Role of PARP.
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.
authors.affiliation: School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton, BN2 4GJ, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Faltz
authors.affiliation: School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton, BN2 4GJ, UK.
authors.forename: Hild
authors.initials: H
authors.lastname: Bergin
authors.affiliation: Brighton and Sussex Medical School, University of Sussex, Brighton, BN1 9PX, UK.
authors.forename: Elly
authors.initials: E
authors.lastname: Pilavachi
authors.affiliation: School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton, BN2 4GJ, UK.
authors.forename: Guy
authors.initials: G
authors.lastname: Grimwade
authors.affiliation: School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton, BN2 4GJ, UK. j.g.mabley@brighton.ac.uk.
authors.forename: Jon G
authors.initials: JG
authors.lastname: Mabley
mesh_terms: D000480:Alkynes; D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology* / Q000633:toxicity; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology; D048588:Benzoxazines / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D000068679:Emtricitabine / Q000494:pharmacology* / Q000633:toxicity; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009924:Organ Culture Techniques; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068698:Tenofovir / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000480:Alkynes; D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D000068698:Tenofovir; D011065:Poly(ADP-ribose) Polymerases; D000068679:Emtricitabine; C098320:efavirenz
keywords: Cardiovascular; Efavirenz; Emtricitabine; Endothelial; Oestrogen; PARP; Tenofovir