Activation of extracellular signal-regulated kinases is essential for pressure-induced proliferation of vascular smooth muscle cells.
In hypertension, increased transmural pressure directly influences vascular smooth muscle cells and causes cell proliferation. However, the mechanisms of transmural pressure-induced proliferation of vascular smooth muscle cells are unknown. We investigated the role of various protein kinases in pressure-induced proliferation of vascular smooth muscle cells. Pressure was applied to quiescent rat vascular smooth muscle cells in culture by compressed helium gas in a loading apparatus. Pressure application increased [3H]thymidine incorporation in a time- and pressure-dependent manner and significantly increased the cell number. The pressor response was significantly suppressed by various protein kinase inhibitors for protein kinase C (bisindolylmaleimide I), tyrosine kinase (genistein), extracellular signal-regulated kinase kinase (PD98059; 2'-amino-3'-methoxyflavone) and p38 mitogen-activated protein kinases (MAPK) (SB203580; 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole). Pressure rapidly increased the phosphorylation and activity of extracellular signal-regulated kinases (ERK). Pressure also caused increment of phosphorylation level of p38 MAPK but not that of c-JUN N-terminal protein kinase (JNK). In ERK-deficient cells prepared by transfection of an antisense oligonucleotide for ERK, pressure-induced DNA synthesis was almost abolished. Our results suggest that activation of ERK is essential for pressure-induced DNA synthesis in rat vascular smooth muscle cells, in addition to activation of protein kinase C, tyrosine kinase and p38 MAPK. These processes could be involved in the pathogenesis of hypertension-related atherosclerosis.
Tsuda
Yuki
Y
The Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi, Kitakyushu, 807-8555, Japan.
Okazaki
Masahiro
M
Uezono
Yasuhito
Y
Osajima
Akihiko
A
Kato
Hiroaki
H
Okuda
Haruhito
H
Oishi
Yosuke
Y
Yashiro
Akira
A
Nakashima
Yasuhide
Y
D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D011312:Pressure; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D016376:Oligonucleotides, Antisense; D011725:Pyridines; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one