School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton, BN2 4GJ, UK.
Brighton and Sussex Medical School, University of Sussex, Brighton, BN1 9PX, UK.
Cardiovasc Toxicol. 2017 Oct;17(4):393-404. doi: 10.1007/s12012-016-9397-4.
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.
高效抗逆转录病毒疗法已被证明可成功降低与 HIV 感染相关的发病率和死亡率，尽管它与心血管疾病风险增加有关。迄今为止，抗逆转录病毒药物依非韦伦、替诺福韦和恩曲他滨对血管舒张反应的直接影响尚未阐明，而这些影响可能使个体易患心血管疾病。细胞氧化应激增加和 DNA 修复酶多聚（ADP-核糖）聚合酶（PARP）过度激活已被确定为血管功能障碍的中心介质。本研究旨在探讨依非韦伦、替诺福韦或恩曲他滨暴露是否通过 PARP 的过度激活直接导致内皮细胞功能障碍。体外雄性大鼠主动脉环或内皮细胞暴露于依非韦伦而不是替诺福韦或恩曲他滨会损害乙酰胆碱介导的舒张反应，增加细胞氧化应激和 PARP 活性，降低细胞活力并增加细胞凋亡和坏死。PARP 的药理学抑制可防止依非韦伦介导的血管舒张功能障碍和内皮细胞功能障碍。雌激素暴露也可防止依非韦伦抑制血管舒张反应、细胞功能障碍和增加的 PARP 激活。总之，依非韦伦直接损害内皮细胞功能，这可能是抗逆转录病毒治疗中增加心血管并发症风险的原因。
