Nordihydroguaiaretic acid (NDGA) inhibits ritonavir-induced endothelial dysfunction in porcine pulmonary arteries

Jian Ming Lü, Jacobo Nurko, Jun Jiang, Sarah M. Weakley, Peter H. Lin, Qizhi Yao, Changyi Chen

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Background: HIV infection and treatment with highly active antiretroviral therapy (HAART) including HIV protease inhibitor ritonavir (RTV) have been associated with endothelial dysfunction and cardiovascular disease including pulmonary arterial hypertension. The objective of this study was to determine if nordihydroguaiaretic acid (NDGA), a natural herbal antioxidant found in the creosote bush Larrea tridentate, can protect vascular tissues against RTV-induced vascular injury. Material/Methods: Fresh porcine pulmonary artery (PA) rings were treated with a clinically relevant concentration of RTV (15 μmol/L) with or without NDGA for 24 hours, and then subjected to myograph analysis for vasomotor reactivity. Expression of endothelial nitric oxide synthase (eNOS) in both treated PA rings and human pulmonary artery endothelial cells (HPAECs) was analyzed by real-time PCR and immunohistochemistry. Oxidative stress levels were analyzed with the lucigenin-enhanced che-miluminescence and glutathione assay. Results: In response to bradykinin at 10-10 mol/L, RTV-treated PA rings showed a 39% reduction in endo-thelium-dependent vasorelaxation compared with the control vessels (P<0.05); when co-cultured with NDGA (1.75 or 3.50 μmol/L), the relaxation increased by 25% and 48%, respectively. RTV also decreased the maximal contraction and endothelium-independent vasorelaxation in RTV-treated vessels, while NDGA improved these vasomotor responses. In addition, treatment of RTV signif-cantly decreased eNOS mRNA levels in both porcine PAs and HPAECs, and reduced eNOS immu-noreactivity in porcine PAs, while NDGA signifcantly inhibited this effect of RTV. Furthermore, NDGA signifcantly blocked RTV-induced increase of superoxide anion in the PA rings and inhibited RTV-induced decrease of glutathione in HPAECs. Conclusions: NDGA effectively inhibits the detrimental effects of HIV protease inhibitor RTV on vasomotor functions in porcine PAs. NDGA also blocks RTV-induced decrease of eNOS expression and increase of oxidative stress in both porcine PAs and HPAECs. This study may provide valuable information for the development of effective strategies for the prevention and treatment of HAART-associated cardiovascular complications.

Original languageEnglish (US)
Pages (from-to)312-318
Number of pages7
JournalMedical Science Monitor
Volume17
Issue number11
DOIs
StatePublished - 2011
Externally publishedYes

Keywords

  • Endothelial dysfunction
  • Endothelial nitric oxide synthase
  • Nordihydroguaiaretic acid
  • Pulmonary artery
  • Reactive oxygen species
  • Ritonavir

ASJC Scopus subject areas

  • Medicine(all)

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