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Vol. 291, Issue 2, 733-738, November 1999
11
Department of Medicine (B.C.Y., J.L.M.), and Pathology and
Laboratory Medicine (D.S.Z.), The outcome of myocardial ischemia-reperfusion has been
partially attributed to the degree of apoptosis in cardiomyocytes. Aggregating platelets by release of transforming growth
factor-
1 (TGF-1) protect the
isolated heart against ischemia-reperfusion injury and preserve
myocardial TGF-1 content. To gain more insight into the
modulation of hypoxia-reoxygenation-induced injury (apoptosis and
necrosis) to myocytes by TGF-1 and aggregating
platelets, cultured adult rat myocytes were exposed for 48 or 72 h
to hypoxia alone, or to hypoxia followed by 3 h of reoxygenation.
Apoptosis in the cells was determined by in situ terminal
deoxynucleotidyl transferase-mediated dUTP-biotin nick end
labeling staining and DNA fragmentation on gel electrophoresis.
Hypoxia alone caused a time-dependent increase in myocyte apoptosis
(number of apoptotic cells: 19 ± 3% at 48 h and 39 ± 5% at 72 h compared with 5 ± 1% in control cells, based on
a 500-cell count). Three hours of reoxygenation after 48 h
of hypoxia further increased the number of apoptotic cells (34 ± 8 versus 19 ± 3% in hypoxia for 48 h), but reoxygenation after 72 h of hypoxia did not additionally increase the number of
apoptotic cells, perhaps because of extensive cell necrosis on
prolonged hypoxia. Forty-eight hours of hypoxia followed by 3 h of
reoxygenation also resulted in a decrease in Bcl-2 and an increase in
Fas protein level. Incubation of myocytes with either recombinant
TGF-1 (0.5-5 ng/ml) or aggregated platelet supernatant
(from 2-3 × 107 platelets/ml, containing ~0.5
ng/ml of TGF-1) markedly (P < .01)
decreased the number of apoptotic cells after hypoxia-reoxygenation. Incubation with TGF-1 also reduced myocyte necrosis as
evident from lactate dehydrogenase release and trypan blue dye
exclusion. These data demonstrate that hypoxia-reoxygenation results in
apoptosis and necrosis in cultured adult rat myocytes; this can be
attenuated by TGF-1. Similarity of data with
TGF-1 and aggregated platelet supernatant suggests that
platelet-mediated cardioprotection during hypoxia-reoxygenation may
relate in part to the release of TGF-1.
0022-3565/99/2912-0733$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics
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