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
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.