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

Nature Medicine volume 7, pages 108–113 (2001)Cite this article

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 single-strand 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.

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Figure 1: Reversal of diabetes-induced endothelial dysfunction by pharmacological inhibition of PARP.
Figure 2: Reactive nitrogen species generation, ssDNA breakage and PARP activation in diabetic blood vessels.
Figure 3: Reactive nitrogen species generation, ssDNA breakage and PARP activation in endothelial cells placed in high glucose.
Figure 4: PARP-deficient vascular rings are resistant against high-glucose–induced loss of endothelial dysfunction.
Figure 5: EMSA analysis of the effect of PARP on NF-κB activation.
Figure 6

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Acknowledgements

This work was supported by grants from the National Institutes of Health to C.S. (R01GM60915 and R21HL65145). F.G.S. was supported by a fellowship from FAPESP (Brazil). L.V. was supported by a Bolyai Fellowship of the hungarian Academy of Sciences and L.L. was supported by the ADUMED Foundation (Switzerland).

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Author notes

  1. Francisco Garcia Soriano and László Virág: F.G.S. and L.V. contributed equally to the work.

Authors and Affiliations

  1. Inotek Corporation, Suite 419E, 100 Cummings Center, Beverly, 01915, Massachusetts, USA

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

  2. Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry New Jersey, 185 University Heights, Newark, 01703, New Jersey, USA

    Francisco Garcia Soriano, Lucas Liaudet & Csaba Szabó

  3. Division of Pharmacology, College of Pharmacy, The Ohio State University, 496 West 12th Avenue, Columbus, 43210, Ohio, USA

    Dale G. Hoyt

  4. Department of Critical Care Medicine, Hospital das Clinicas da Universidade de Sao Paulo, Sao Paulo, Brazil

    Francisco Garcia Soriano

  5. Department of Internal Medicine, Critical Care Division, University Hospital, Lausanne, Switzerland

    Lucas Liaudet

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Correspondence to Csaba Szabó.

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Garcia Soriano, F., Virág, L., Jagtap, P. et al. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med 7, 108–113 (2001). https://doi.org/10.1038/83241

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