Inhibition of C-Jun N-Terminal Kinase 1, but Not c-Jun N-Terminal Kinase 2, Suppresses Apoptosis Induced by Ischemia/Reoxygenation in Rat Cardiac Myocytes
In the present study, rat cardiac myocytes were used as an in vitro ischemia/reperfusion injury model to delineate the role of c-Jun N-terminal kinase (JNK) 1 and JNK2 isoforms in ischemia/reoxygenation-induced apoptosis using an antisense approach. Exposure of rat cardiac myocytes to ischemia did n...
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Published in | Molecular pharmacology Vol. 59; no. 4; pp. 867 - 874 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.04.2001
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Subjects | |
Online Access | Get full text |
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Summary: | In the present study, rat cardiac myocytes were used as an in vitro ischemia/reperfusion injury model to delineate the role
of c-Jun N-terminal kinase (JNK) 1 and JNK2 isoforms in ischemia/reoxygenation-induced apoptosis using an antisense approach.
Exposure of rat cardiac myocytes to ischemia did not induce apoptosis as detected by staining with either acridine orange/ethidium
bromide or annexin-V-fluorescein/propidium iodide. In contrast, a time-dependent increase in the number of apoptotic cells
was noted after reoxygenation of ischemic myocytes, whereas the level of necrotic cells remained unaltered. Reoxygenation,
but not ischemia alone, also caused a time-dependent increase in JNK activation that preceded apoptosis induction. Treatment
of cardiac myocytes with antisense (AS) oligonucleotides that specifically targeted either JNK1 or JNK2 significantly reduced
both mRNA and protein expression of the target isoform but had no effect on the expression of the alternate isoform. Pretreatment
of cardiac myocytes with JNK1 AS, but not JNK2 AS, resulted in almost complete attenuation of reoxygenation-induced apoptosis.
Furthermore, control oligonucleotides for JNK1 AS or JNK2 AS had no effect on JNK mRNA or protein expression or reoxygenation-induced
apoptosis, indicating a sequence-specific mode of action. Additional studies revealed that apoptosis induced by other JNK-activating
stimuli, including ceramide, heat shock, and UV irradiation, was partly suppressed after treatment with JNK1 AS but not JNK2
AS. These findings demonstrate that the JNK1 isoform plays a preferential role in apoptosis induced by ischemia/reoxygenation
as well as diverse JNK-activating cellular stresses. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.59.4.867 |