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

Citation
Il. Grupp et al., Protection against hypoxia-reoxygenation in the absence of poly (ADP-ribose) synthetase in isolated working hearts, J MOL CEL C, 31(1), 1999, pp. 297-303
Citations number
40
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
ISSN journal
00222828 → ACNP
Volume
31
Issue
1
Year of publication
1999
Pages
297 - 303
Database
ISI
SICI code
0022-2828(199901)31:1<297:PAHITA>2.0.ZU;2-Q
Abstract
Peroxynitrite and hydroxyl radical are reactive oxidants produced during my ocardial reperfusion injury. They have been shown to induce dysfunction in cardiac myocytes, in part, via the activation of the nuclear enzyme poly (A DP-ribose) synthetase (PARS). These oxidants can trigger DNA single strand breakage, which triggers PARS activation, resulting in cellular NAD(+) and ATP depletion and cytotoxicity. Recent work has demonstrated that hypoxia-r eoxygenation of cardiac myocytes in vitro also causes peroxynitrite formati on, PARS activation and cytotoxicity. In the present study. using hearts fr om genetically engineered mice lacking PARS, we have investigated whether t he absence of PARS alters the functional response to hypoxia reoxygenation. Isolated work-performing mouse hearts were stabilized under the same loadi ng 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 th e 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 reoxyge nation, in hearts from wild-type animals, there was a significant suppressi on in the rate of intraventricular pressure development (+dP/dt) from 3523 to 2907 mmHg. There was also a significant suppression in the rate of relax ation (- dP/dt) in the wild-type hearts from 3123 to 2168 mmHg, The time to peak pressure (TPP) increased from 0.45 to 0.59 ms/mmHg and the half-time of relaxation (RT1/2) increased from 0.59 to 0.74 ms/mmHg, In contrast, in the hearts from the PARS knockout animals, no significant suppression of +d P/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 partia lly ameliorated (from 3399 to 2687 mmHg) as well as the half-time of relaxa tion (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 s uppression of the myocardial contractility is dependent on the functional i ntegrity of PARS. (C) 1999 Academic Press.