Manipulating glutathione-S-transferases may prevent the development of tolerance to nitroglycerin

Liansheng Wang, Yongzhen Yang, Seema Dwivedi, Ya Xu, Etem T. Chu, Jie Li, Kimberlyn Fitchett, Paul J. Boor

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Tolerance to clinically important organic nitrates such as nitroglycerin (NTG) has been experimentally related to endothelial dysfunction and vascular oxidative stress. Anti-oxidant enzymes such as the glutathione-S-transferases GSTs) could potentially play a protective role in NTG tolerance. Our previous work showed that an α-class glutathione-S-transferase (GSTA4-4) defends against oxidative damage in the vascular wall; therefore, we asked whether overexpression of GSTA4-4 in endothelial cells and smooth muscle cells might alter the development of tolerance to NTG. Stable transfections of mouse pancreatic islet endothelial cells (MS1) with cDNA of mGSTA4-4, and human fetal aortic vascular smooth muscle cells (FLTR) with cDNA of hGSTA4-4 were established. MTT cytotoxicity, apoptosis, nitric oxide (NO) synthases, both endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) and cyclic guanosine mono-phosphate (cGMP) were measured. Endothelial cells overexpressing mGSTA4-4, and smooth muscle cells overexpressing hGSTA4-4 were more resistant to cytotoxic injury by NTG, assessed at 24 h (p < 0.05). In both endothelial and smooth muscle cells, NTG-induced apoptosis was inhibited by GST overexpression. Following dosing in a relevant tolerance-inducing NTG protocol, we found that GSTA4-4-overexpressing cells demonstrated significant downregulation of NOS enzymes; NO release, unchanged by the tolerance protocol in both wild-type and vector-transfected cells, was augmented in GST-overexpressing cells (p < 0.01); cGMP levels in control cells fell, whereas it rose in GSTA4-4-overexpressing cells (p < 0.05). Our results demonstrate that overexpression of GST isozymes can protect endothelial cells and smooth muscle cells against oxidative stress associated with NTG, and markedly alter cellular responses to repeated doses, or tolerance. By manipulating GSTs, physiological tolerance to NTG may be diminished or eliminated.

Original languageEnglish (US)
Pages (from-to)131-144
Number of pages14
JournalCardiovascular Toxicology
Volume6
Issue number2
DOIs
StatePublished - Jun 2006

Fingerprint

Nitroglycerin
Glutathione Transferase
Smooth Muscle Myocytes
Endothelial cells
Muscle
Cells
Endothelial Cells
Oxidative stress
Guanine Nucleotides
Guanosine
Islets of Langerhans
Blood Vessels
Oxidative Stress
Complementary DNA
Phosphates
Apoptosis
Nitric Oxide Synthase Type III
Nitric oxide
Nitric Oxide Synthase Type II
Enzymes

Keywords

  • Drug tolerance
  • Endothelium
  • Glutathione S-transferase (GST)
  • Nitroglycerin (NTG)
  • Vascular smooth muscle cell, oxidative stress

ASJC Scopus subject areas

  • Toxicology
  • Cardiology and Cardiovascular Medicine

Cite this

Wang, L., Yang, Y., Dwivedi, S., Xu, Y., Chu, E. T., Li, J., ... Boor, P. J. (2006). Manipulating glutathione-S-transferases may prevent the development of tolerance to nitroglycerin. Cardiovascular Toxicology, 6(2), 131-144. https://doi.org/10.1385/CT:6:2:131

Manipulating glutathione-S-transferases may prevent the development of tolerance to nitroglycerin. / Wang, Liansheng; Yang, Yongzhen; Dwivedi, Seema; Xu, Ya; Chu, Etem T.; Li, Jie; Fitchett, Kimberlyn; Boor, Paul J.

In: Cardiovascular Toxicology, Vol. 6, No. 2, 06.2006, p. 131-144.

Research output: Contribution to journalArticle

Wang, L, Yang, Y, Dwivedi, S, Xu, Y, Chu, ET, Li, J, Fitchett, K & Boor, PJ 2006, 'Manipulating glutathione-S-transferases may prevent the development of tolerance to nitroglycerin', Cardiovascular Toxicology, vol. 6, no. 2, pp. 131-144. https://doi.org/10.1385/CT:6:2:131
Wang, Liansheng ; Yang, Yongzhen ; Dwivedi, Seema ; Xu, Ya ; Chu, Etem T. ; Li, Jie ; Fitchett, Kimberlyn ; Boor, Paul J. / Manipulating glutathione-S-transferases may prevent the development of tolerance to nitroglycerin. In: Cardiovascular Toxicology. 2006 ; Vol. 6, No. 2. pp. 131-144.
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