© 1997 American Heart Association, Inc.
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Evidence That Angiotensin II and Lipoxygenase Products Activate c-Jun NH2-Terminal Kinase
From the Department of Diabetes, Endocrinology and Metabolism, City of Hope Medical Center, Duarte, Calif.
Correspondence to Jerry L Nadler, MD, Department of Diabetes, Endocrinology and Metabolism, City of Hope Medical Center, 1500 East Duarte Rd, Shapiro 106, Duarte, CA 91010. E-mail jnadler{at}smtplink.coh.org
Abstract The effect of angiotensin II (Ang II) to
activate c-Jun amino-terminal kinase (JNK) was studied in a
Chinese hamster ovary fibroblast cell line overexpressing the rat
vascular type-1a Ang II receptor (CHO-AT1a). Ang II
treatment induced a time-dependent activation of JNK. Ang II
(10-7 mol/L) activated JNK activity,
with a peak at 30 minutes (9.39±2.52-fold, n=7, P<.02
versus control), which was maintained until 3 hours (2.7±0.65-fold,
n=3, P<.02 versus control). Ang II–induced JNK activation
at 30 minutes was inhibited by a specific lipoxygenase
(LO) pathway inhibitor,
cinnamyl-3,4-dihydroxy-
-cyanocinnamate (1 µmol/L) by 87.5%
(n=4, P<.01 versus Ang II–induced JNK activity). The
direct addition of 12-HETE also induced a time-dependent JNK
activation. 12-HETE (10-7 mol/L)
activated JNK activity, with a peak at 10 minutes
(3.43±0.87-fold, n=6, P<.02 versus control), which
remained elevated until 1 hour. These results suggest that the LO
pathway is a mediator of Ang II–induced JNK activation. 15-HETE can
also activate JNK at 5 minutes, but this activity was reduced
at 30 minutes and could not be seen at 1 hour, indicating that the time
course was different from that seen with 12-HETE.
N-Acetylcysteine (NAC), an antioxidant, was used to perturb
intracellular reactive oxygen intermediate (ROI) levels to assess the
role of endogenous ROIs in regulating JNK activity.
Pretreatment of cells with 500 µmol/L NAC for 1 hour attenuated
50% of Ang II–induced JNK activation, suggesting that ROIs, at
least partially, mediate Ang II–induced JNK activation. Furthermore,
12-HETE–induced JNK activation was reduced by 90% by NAC. Finally,
pertussis toxin completely blocked 12-HETE–induced JNK activation,
suggesting that Gi-protein signaling participates in
12-HETE–induced effects. These results suggest that LO activation
plays a role in mediating Ang II–induced JNK activation in part by
altering the redox tone and Gi-protein signaling of cells.
Key Words: angiotensin II • 12-HETE • c-Jun NH2-terminal kinase • lipoxygenase
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