Influence of age on hypoxia/reoxygenation-induced DNA fragmentation and Bcl-2, Bcl-xl, Bax and Fas in the rat heart and brain

To test the hypothesis that the aging mammalian heart and brain might have increased vulnerability to acute stress, DNA fragmentation was studied after hypoxia-reoygenation in young adult (6 months) and old (22-24 months) F344 rats. Heart and brain tissue were examined at the following time points: 30, 60, or 90 min of hypoxia (H, 5% O-2, 95% N-2) plus 2 h of reoxygenation (R, room air, 21% O-2). With increasing duration of hypoxia preceding the reoxygenation, the extent of DNA fragmentation tin situ terminal dUTP nick end labeling, TUNEL, positive cells) was progressively higher in both age groups, greater in the old compared to that of the young adult rat. The levels of the anti-apoptotic proteins bcl-2 and bcl-x(L), were similar in young and old at baseline and tended to increase in both age groups after hypoxia/reoxygenation. The pro-apoptotic protein, bax, was higher at baseline in the old; it rose after hypoxia/reoxygenation in the young adult heart and brain, but was unchanged in the old heart and was decreased in the old brain. The ratios of bcl-2/bax and of bcl-x(L)/bax were higher in the old heart and brain compared to that in the young adult after hypoxia/reoxygenation. Thus, compared to that of the young adult, the heart and brain of the old rat have lower thresholds and ape more vulnerable to injury induced by hypoxia/reoxygenation, despite rapid and heightened expression of the anti-apoptotic proteins bcl-2 and bcl-xl. This could be due partly to the age-associated increase in the basal expression of the pro-apoptotic protein bax, as well as possibly other factors. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.