p38 Mitogen-activated protein kinase is a critical component of the redox-sensitive signaling pathways activated by angiotensin II. Role in vascular smooth muscle cell hypertrophy.

J Biol Chem 1998 Jun;273(24):15022-9

Department of Medicine, Division of Cardiology, Emory University, Atlanta, Georgia 30322, USA.

Angiotensin II induces an oxidant stress-dependent hypertrophy in cultured vascular smooth muscle cells. To investigate the growth-related molecular targets of H2O2, we examined the redox sensitivity of agonist-stimulated activation of the mitogen-activated protein kinase (MAPK) family. We show here that angiotensin II elicits a rapid increase in intracellular H2O2 and a rapid and robust phosphorylation of both p42/44MAPK (16-fold) and p38MAPK (15-fold). However, exogenous H2O2 activates only p38MAPK (14-fold), and diphenylene iodonium, an NADH/NADPH oxidase inhibitor, attenuates angiotensin II-stimulated phosphorylation of p38MAPK, but not p42/44MAPK. Furthermore, in cells stably transfected with human catalase, angiotensin II-induced intracellular H2O2 generation is almost completely blocked, resulting in inhibition of phosphorylation of p38MAPK, but not p42/44MAPK, and a subsequent partial decrease in angiotensin II-induced hypertrophy. Specific inhibition of either the p38MAPK pathway with SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H- imidaz ole) or the p42/44MAPK pathway with PD98059 (2-(2'-amino-3'-methoxyphenyl)oxanaphthalen-4-one) also partially, but significantly, attenuates angiotensin II-induced hypertrophy; however, simultaneous blockade of both pathways has an additive inhibitory effect, indicating that the hypertrophic response to angiotensin II requires parallel, independent activation of both MAPK pathways. These results provide the first evidence that p38MAPK is a critical component of the oxidant stress (H2O2)-sensitive signaling pathways activated by angiotensin II in vascular smooth muscle cells and indicate that it plays a crucial role in vascular hypertrophy.

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.273.24.15022DOI Listing
June 1998
2 Reads

Publication Analysis

Top Keywords

angiotensin ii-induced
12
smooth muscle
12
vascular smooth
12
angiotensin
9
activated angiotensin
8
pathways activated
8
signaling pathways
8
attenuates angiotensin
8
role vascular
8
ii-induced hypertrophy
8
muscle cells
8
mitogen-activated protein
8
phosphorylation p38mapk
8
intracellular h2o2
8
p38mapk p42/44mapk
8
critical component
8
protein kinase
8
p38mapk
6
hypertrophy
5
ii-induced intracellular
4

References

(Supplied by CrossRef)

Boscoboinik et al.
J. Biol. Chem. 1991

Similar Publications