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 Szabó

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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
Pages (from-to)108-113
Number of pages6
JournalNature medicine
Volume7
Issue number1
DOIs
Publication statusPublished - Feb 5 2001

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Garcia Soriano, F., Virág, L., Jagtap, P., Szabó, É., Mabley, J. G., Liaudet, L., Marton, A., Hoyt, D. G., Murthy, K. G. K., Salzman, A. L., Southan, G. J., & Szabó, 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