期刊
BIOCHEMICAL PHARMACOLOGY
卷 59, 期 8, 页码 937-945出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0006-2952(99)00418-9
关键词
ischemia-reperfusion; free radicals; reactive oxygen species; cell damage; signal; heart perfusion; BGP-15; poly(ADP-ribose) polymerase; GRP78; lipid peroxidation; chaperone
The protective effect of O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime (BGP-15) against ischemia-reperfusion-induced injury was studied in the Langendorff heart perfusion system. To understand the molecular mechanism of the cardioprotection, the effect of BGP-15 on-ischemic-reperfusion induced reactive oxygen species (ROS) formation, lipid peroxidation single-strand DNA break formation, NAD(+) catabolism, and endogenous ADP-ribosylation reactions were investigated. These studies showed that BGP-15 significantly decreased leakage of lactate dehydrogenase, creatine kinase, and aspartate aminotransferase in reperfused hearts, and reduced the rate of NAD(+) catabolism. In addition, BGP-15 dramatically decreased the ischemia-reperfusion induced self-ADP-ribosylatipn of nuclear poly(ADP-ribose) polymerase(PARP) and the mono-ADP-ribosylation of an endoplasmic reticulum chaperone GRP78. These data raise the possibility that BGP-15 may have a direct inhibitory effect on PARP. This hypothesis was tested on isolated enzyme, and kinetic analysis showed a mixed-type (noncompetitive) inhibition with a K-i = 57 +/- 6 mu M. Furthermore, BGP-15 decreased levels of ROS, lipid peroxidation, and single strand DNA breaks in reperfused hearts. These data suggest that PARP may be an important molecular target of BGP-15 and that BGP-15 decreases ROS levels and cell injury during ischemia-reperfusion in the heart by inhibiting PARP activity. (C) 2000 Elsevier Science Inc.
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