Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase

Francisco Garcia Soriano, Pál Pacher, Jon Mabley, Lucas Liaudet, Csaba Szabó

    Research output: Contribution to journalArticle

    168 Scopus citations

    Abstract

    Oxygen- and nitrogen-derived free radicals and oxidants play an important role in the pathogenesis of diabetic endothelial dysfunction. Recently we proposed the importance of oxidant-induced DNA strand breakage and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) in the pathogenesis of diabetic endothelial dysfunction. In this study, we tested whether established diabetic endothelial dysfunction is reversible by PARP inhibition. The novel PARP inhibitor PJ34 (10 mg/kg per day PO) was given at various lengths (4 weeks or 3 days) for established streptozotocin-diabetic animals. In addition, we also tested whether incubation of the aortic rings with PJ34 (3 μmol/L) or a variety of other PARP inhibitors for 1 hour affects the diabetic vascular changes. Both 4-week and 3-day PARP-inhibitor treatment of streptozotocin-diabetic mice with established endothelial dysfunction fully reversed the acetylcholine-induced endothelium-dependent relaxations in vitro. Furthermore, 1-hour in vitro incubation of aortae from streptozotocin-diabetic mice with various PARP inhibitors was able to reverse the endothelial dysfunction. ATP, NAD+, and NADPH levels were markedly reduced in diabetic animals, and PARP-inhibitor treatment was able to restore these alterations. Unexpectedly, pharmacological inhibition of PARP not only prevents the development of the endothelial dysfunction but is also able to rapidly reverse it. Thus, PARP activation and the associated metabolic compromise represent an ongoing process in diabetic blood vessels. Pharmacological inhibition of this process is able to reverse diabetic endothelial dysfunction.

    Original languageEnglish (US)
    Pages (from-to)684-691
    Number of pages8
    JournalCirculation Research
    Volume89
    Issue number8
    DOIs
    StatePublished - Oct 12 2001

    Keywords

    • Apoptosis
    • Diabetes
    • Endothelium
    • Necrosis
    • Nitric oxide

    ASJC Scopus subject areas

    • Physiology
    • Cardiology and Cardiovascular Medicine

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