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Vol. 59, Issue 4, 867-874, April 2001
Department of Metabolic and Cardiovascular Diseases, Novartis
Institute for Biomedical Research, Summit, New Jersey (D.H., M.G.,
C.L.C.); and Department of Molecular Pharmacology, ISIS
Pharmaceuticals, Carlsbad, California (W.G., B.P.M., R.A.M.)
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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