Nitroglycerin tolerance in caveolin-1 deficient mice

Mao Mao, Sudhahar Varadarajan, Tohru Fukai, Farnaz R. Bakhshi, Olga Chernaya, Samuel C. Dudley, Richard D. Minshall, Marcelo G. Bonini

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Nitrate tolerance developed after persistent nitroglycerin (GTN) exposure limits its clinical utility. Previously, we have shown that the vasodilatory action of GTN is dependent on endothelial nitric oxide synthase (eNOS/NOS3) activity. Caveolin-1 (Cav-1) is known to interact with NOS3 on the cytoplasmic side of cholesterol-enriched plasma membrane microdomains (caveolae) and to inhibit NOS3 activity. Loss of Cav-1 expression results in NOS3 hyperactivation and uncoupling, converting NOS3 into a source of superoxide radicals, peroxynitrite, and oxidative stress. Therefore, we hypothesized that nitrate tolerance induced by persistent GTN treatment results from NOS3 dysfunction and vascular toxicity. Exposure to GTN for 48-72 h resulted in nitrosation and depletion (>50%) of Cav-1, NOS3 uncoupling as measured by an increase in peroxynitrite production (>100%), and endothelial toxicity in cultured cells. In the Cav-1 deficient mice, NOS3 dysfunction was accompanied by GTN tolerance (>50% dilation inhibition at low GTN concentrations). In conclusion, GTN tolerance results from Cav-1 modification and depletion by GTN that causes persistent NOS3 activation and uncoupling, preventing it from participating in GTN-medicated vasodilation.

Original languageEnglish (US)
Article numbere104101
JournalPLoS One
Volume9
Issue number8
DOIs
StatePublished - Aug 26 2014
Externally publishedYes

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Caveolin 1
Nitroglycerin
mice
Peroxynitrous Acid
Nitrates
Toxicity
Nitrosation
Membrane Microdomains
Caveolae
Oxidative stress
Nitric Oxide Synthase Type III
Cell membranes
Vasodilation
Superoxides
Blood Vessels
Dilatation
Cultured Cells
Oxidative Stress
Chemical activation
Cholesterol

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Mao, M., Varadarajan, S., Fukai, T., Bakhshi, F. R., Chernaya, O., Dudley, S. C., ... Bonini, M. G. (2014). Nitroglycerin tolerance in caveolin-1 deficient mice. PLoS One, 9(8), [e104101]. https://doi.org/10.1371/journal.pone.0104101

Nitroglycerin tolerance in caveolin-1 deficient mice. / Mao, Mao; Varadarajan, Sudhahar; Fukai, Tohru; Bakhshi, Farnaz R.; Chernaya, Olga; Dudley, Samuel C.; Minshall, Richard D.; Bonini, Marcelo G.

In: PLoS One, Vol. 9, No. 8, e104101, 26.08.2014.

Research output: Contribution to journalArticle

Mao, M, Varadarajan, S, Fukai, T, Bakhshi, FR, Chernaya, O, Dudley, SC, Minshall, RD & Bonini, MG 2014, 'Nitroglycerin tolerance in caveolin-1 deficient mice', PLoS One, vol. 9, no. 8, e104101. https://doi.org/10.1371/journal.pone.0104101
Mao, Mao ; Varadarajan, Sudhahar ; Fukai, Tohru ; Bakhshi, Farnaz R. ; Chernaya, Olga ; Dudley, Samuel C. ; Minshall, Richard D. ; Bonini, Marcelo G. / Nitroglycerin tolerance in caveolin-1 deficient mice. In: PLoS One. 2014 ; Vol. 9, No. 8.
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