Diabetic endothelial dysfunction: The role of poly(ADP-ribose) polymerase activation

Francisco Garcia Soriano, László Virág, Prakash Jagtap, Éva Szabó, Jon G. Mabley, Lucas Liaudet, Anita Marton, Dale G. Hoyt, Kanneganti G K Murthy, Andrew L. Salzman, Garry J. Southan, Csaba Szabo

Research output: Contribution to journalArticle

504 Citations (Scopus)

Abstract

Diabetic patients frequently suffer from retinopathy, nephropathy, neuropathy and accelerated atherosclerosis. The loss of endothelial function precedes these vascular alterations. Here we report that activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of endothelial dysfunction in diabetes. Destruction of islet cells with streptozotocin in mice induced hyperglycemia, intravascular oxidant production, DNA strand breakage, PARP activation and a selective loss of endothelium-dependent vasodilation. Treatment with a novel potent PARP inhibitor, starting after the time of islet destruction, maintained normal vascular responsiveness, despite the persistence of severe hyperglycemia. Endothelial cells incubated in high glucose exhibited production of reactive nitrogen and oxygen species, consequent singlestrand DNA breakage, PARP activation and associated metabolic and functional impairment. Basal and high-glucose-induced nuclear factor-κB activation were suppressed in the PARP-deficient cells. Our results indicate that PARP may be a novel drug target for the therapy of diabetic endothelial dysfunction.

Original languageEnglish (US)
Pages (from-to)108-113
Number of pages6
JournalNature Medicine
Volume7
Issue number1
DOIs
StatePublished - 2001
Externally publishedYes

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Poly(ADP-ribose) Polymerases
Chemical activation
Hyperglycemia
Blood Vessels
Reactive Nitrogen Species
Glucose
DNA
Endothelial cells
Streptozocin
Medical problems
Islets of Langerhans
Oxidants
Vasodilation
Endothelium
Reactive Oxygen Species
Atherosclerosis
Endothelial Cells
Drug Therapy
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Garcia Soriano, F., Virág, L., Jagtap, P., Szabó, É., Mabley, J. G., Liaudet, L., ... Szabo, C. (2001). Diabetic endothelial dysfunction: The role of poly(ADP-ribose) polymerase activation. Nature Medicine, 7(1), 108-113. https://doi.org/10.1038/83241

Diabetic endothelial dysfunction : The role of poly(ADP-ribose) polymerase activation. / Garcia Soriano, Francisco; Virág, László; Jagtap, Prakash; Szabó, Éva; Mabley, Jon G.; Liaudet, Lucas; Marton, Anita; Hoyt, Dale G.; Murthy, Kanneganti G K; Salzman, Andrew L.; Southan, Garry J.; Szabo, Csaba.

In: Nature Medicine, Vol. 7, No. 1, 2001, p. 108-113.

Research output: Contribution to journalArticle

Garcia Soriano, F, Virág, L, Jagtap, P, Szabó, É, Mabley, JG, Liaudet, L, Marton, A, Hoyt, DG, Murthy, KGK, Salzman, AL, Southan, GJ & Szabo, C 2001, 'Diabetic endothelial dysfunction: The role of poly(ADP-ribose) polymerase activation', Nature Medicine, vol. 7, no. 1, pp. 108-113. https://doi.org/10.1038/83241
Garcia Soriano F, Virág L, Jagtap P, Szabó É, Mabley JG, Liaudet L et al. Diabetic endothelial dysfunction: The role of poly(ADP-ribose) polymerase activation. Nature Medicine. 2001;7(1):108-113. https://doi.org/10.1038/83241
Garcia Soriano, Francisco ; Virág, László ; Jagtap, Prakash ; Szabó, Éva ; Mabley, Jon G. ; Liaudet, Lucas ; Marton, Anita ; Hoyt, Dale G. ; Murthy, Kanneganti G K ; Salzman, Andrew L. ; Southan, Garry J. ; Szabo, Csaba. / Diabetic endothelial dysfunction : The role of poly(ADP-ribose) polymerase activation. In: Nature Medicine. 2001 ; Vol. 7, No. 1. pp. 108-113.
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