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Troglitazone inhibits angiotensin II‐induced extracellular signal‐regulated kinase 1/2 nuclear translocation and activation in vascular smooth muscle cells
Author(s) -
Goetze Stephan,
Xi Xiao-Ping,
Graf Kristof,
Fleck Eckart,
Hsueh Willa A.,
Law Ronald E.
Publication year - 1999
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(99)00624-9
Subject(s) - ask1 , mitogen activated protein kinase kinase , troglitazone , microbiology and biotechnology , map2k7 , map kinase kinase kinase , angiotensin ii , cyclin dependent kinase 9 , cyclin dependent kinase 2 , protein kinase a , mitogen activated protein kinase 3 , integrin linked kinase , signal transduction , biology , chemistry , kinase , biochemistry , peroxisome , receptor , gene
The thiazolidinedione troglitazone inhibits angiotensin II‐induced extracellular signal‐regulated kinase 1/2 mitogen‐activated protein kinase activity in vascular smooth muscle cells. Activation of extracellular signal‐regulated kinase 1/2 by angiotensin II is a multistep process involving both its phosphorylation by mitogen‐activated protein kinase extracellular signal‐regulated kinase kinase in the cytoplasm and a subsequent translocation to the nucleus. The cytoplasmic activation of extracellular signal‐regulated kinase 1/2 in vascular smooth muscle cells proceeds through the protein kinase Cζ→mitogen‐activated protein kinase extracellular signal‐regulated kinase kinase→extracellular signal‐regulated kinase pathway. Troglitazone did not affect the angiotensin II‐induced activation of protein kinase Cζ or its downstream signaling kinases extracellular signal‐regulated kinase 1/2 in the cytosol. In contrast, angiotensin II‐induced activation of protein kinase Cζ and extracellular signal‐regulated kinase 1/2 in the nucleus were both inhibited by troglitazone. Nuclear translocation of extracellular signal‐regulated kinase 1/2 induced by angiotensin II was completely blocked by troglitazone. Protein kinase Cζ, however, did not translocate upon angiotensin II stimulation. Troglitazone, therefore, inhibits both angiotensin II‐induced nuclear translocation of extracellular signal‐regulated kinase 1/2 and the nuclear activity of its upstream signaling kinase protein kinase Cζ. Since extracellular signal‐regulated kinase 1/2 nuclear translocation may be a critical signaling step for multiple growth factors that stimulate vascular smooth muscle cells proliferation and migration, troglitazone may provide a new therapeutical approach for the prevention and treatment of atherosclerosis and restenosis.