Roles and mechanisms of human immunodeficiency virus protease inhibitor ritonavir and other anti-human immunodeficiency virus drugs in endothelial dysfunction of porcine pulmonary arteries and human pulmonary artery endothelial cells

Am J Pathol. 2009 Mar;174(3):771-81. doi: 10.2353/ajpath.2009.080157. Epub 2009 Feb 13.


The objective of this study was to determine the effects of highly active antiretroviral therapy (HAART) drugs on pulmonary endothelial function. Porcine pulmonary arteries or human pulmonary arterial endothelial cells (HPAECs) were incubated with eight HAART drugs [ritonavir, indinavir, lopinavir, zidovudine (AZT), abacavir, stavudine, didanosine (ddI), and lamivudine] individually or in combination [three HAART drugs (3-plex; indinavir, stavudine, and ddI)] at their clinical plasma concentrations for 24 hours. Endothelium-dependent vasorelaxation in response to bradykinin was reduced significantly by the ritonavir in a concentration-dependent manner. Five other HAART drugs (indinavir, lamivudine, abacavir, AZT, and ddI) and the 3-plex significantly also impaired endothelium-dependent vasorelaxation in response to bradykinin. Five HAART drugs (ritonavir, indinavir, lamivudine, abacavir, and AZT) significantly decreased endothelial nitric oxide synthase (eNOS) expression and increased superoxide anion levels in both vessels and HPAECs. Furthermore, both ritonavir and AZT substantially activated ERK2 in HPAECs. Additionally, the antioxidants ginsenoside Rb1 and ginkgolide A effectively reversed HAART drug-induced vasomotor dysfunction and eNOS down-regulation. Inhibition of ERK1/2 also partially blocked ritonavir- and AZT-induced down-regulation of eNOS and vasomotor dysfunction. Thus, HAART drugs significantly impair endothelial functions of porcine pulmonary arteries and HPAECs, which may be mediated by eNOS down-regulation, oxidative stress, and ERK1/2 activation. These findings suggest that HAART drugs may contribute to the high incidence of pulmonary artery hypertension in human immunodeficiency virus-infected patients.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antiretroviral Therapy, Highly Active / adverse effects
  • Bradykinin / pharmacology
  • Cell Culture Techniques
  • DNA Primers
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / pathology*
  • HIV Protease Inhibitors / adverse effects
  • HIV Protease Inhibitors / blood
  • Nitric Oxide Synthase Type III / drug effects
  • Nitric Oxide Synthase Type III / genetics
  • Pulmonary Artery / cytology
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / pathology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ritonavir / adverse effects*
  • Ritonavir / blood
  • Superoxides / metabolism
  • Swine
  • Vasodilation / drug effects


  • DNA Primers
  • HIV Protease Inhibitors
  • Superoxides
  • Nitric Oxide Synthase Type III
  • Ritonavir
  • Bradykinin