Protection against hypoxia-reoxygenation in the absence of poly (ADP ribose) synthetase in isolated working hearts

Ingrid L. Grupp, Traci M. Jackson, Paul Hake, Gunther Grupp, Csaba Szabó

    Research output: Contribution to journalArticle

    57 Scopus citations

    Abstract

    Peroxynitrite and hydroxyl radical are reactive oxidants produced during myocardial reperfusion injury. They have been shown to induct dysfunction in cardiac myocytes, in part, via the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). These oxidants work has demonstrated that hypoxia-reoxygenation of cardiac myocytes in vitro also causes peroxynitrite formation, PARS activation and cytotoxicity. In the present study, using hearts from genetically engineered mice lacking PARS, we have investigated whether the absence of PARS alters the functional response to hypoxia reoxygenation. Isolated work-performing mouse hearts were stabilized under the same loading condition (cardiac minute work of 250 mmHg x ml/min, an afterload of 50 mmHg aortic pressure and similar venous return of 5 ml/min, resulting in the same preload). After 30 min equilibration the hearts were subjected to 30 min hypoxia followed by 30 min of reoxygenation. At the end of the reoxygenation, in hearts from wild-type animals, there was a significant suppression in the rate of intraventricular pressure development (+ dP/dt) from 3523 to 2907 mmHg. There was also a significant suppression in the rate of relaxation ( - dP/dt) in the wild-type hearts from 3123 to 2168 mmHg. The time to peak pressure (TPP) increased from 0.48 to 0.59 ms/mmHg and the half-time of relaxation (RT(1/2)) increased from 0.59 to 0.74 ms/mmHg. In contrast, in the hearts from the PARS knockout animals, no significant suppression of + dP/dt (from 3654 to 3419 mmHg), and no significant increase in the TPP (from 0.462 to 0.448 ms/mmHg) were found, and the decrease in - dP/dt was partially ameliorated (from 3399 to 2687 mmHg) as well as the half-time of relaxation (from 0.507 to 0.55 ms/mmHg) when compared to the response to the wild-type hearts. The current data demonstrate that the reoxygenation induced suppression of the myocardial contractility is dependent on the functional integrity of PARS.

    Original languageEnglish (US)
    Pages (from-to)297-303
    Number of pages7
    JournalJournal of Molecular and Cellular Cardiology
    Volume31
    Issue number1
    DOIs
    StatePublished - Jan 1999

    Keywords

    • Cardiac myocytes
    • Nitric oxide
    • Peroxynitrite
    • Reperfusion
    • Superoxide

    ASJC Scopus subject areas

    • Molecular Biology
    • Cardiology and Cardiovascular Medicine

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