Intracellular signal transduction modulating expression of plasminogen activator inhibitor-1 in adipocytes.
The concentrations in blood of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis and proteolysis, are elevated in obese and insulin-resistant subjects, predispose them to the risk of thrombosis, and may accelerate atherogenesis. Adipose tissue is a prominent source. Accordingly, intracellular signaling pathways that may influence PAI-1 expression in adipocytes have been the focus of considerable study. Rho, a small GTP binding and GTPase protein, when activated in turn activates its target, Rho-associated coiled-coil forming protein, to yield an active kinase, Rho-kinase, an effector in the Rho pathway. Rho-kinase exerts calcium-sensitizing effects in vascular smooth muscle cells and inhibitory effects on transforming growth factor-beta (TGF-beta) expression in chicken embryonic heart cells. Because TGF-beta is a powerful agonist of PAI-1 expression, we characterized the effects of inhibition of Rho-kinase in 3T3-L1 adipocytes. PAI-1 mRNA was determined by Northern blotting, and PAI-1 protein was determined by Western blotting. The Rho-kinase inhibitor, Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide], increased PAI-1 expression markedly. Although genistein, a flavonoid tyrosine kinase, attenuated the increase of PAI-1 induced by Y-27632, other non-flavonoid tyrosine kinase inhibitors did not. However, another flavonoid, daidzein, which lacks tyrosine kinase activity, decreased basal PAI-1 expression and attenuated the induction of PAI-1 expression by Y-27632. Thus, the Rho/Rho-kinase system inhibits PAI-1 expression by a flavonoid-sensitive mechanism in adipocytes. Therefore, flavonoids may be useful in decreasing elevated PAI-1 expression in adipose tissue and its consequent pathophysiologic sequelae.
Goto
Daisuke
D
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Fujii
Satoshi
S
Kaneko
Takeaki
T
Furumoto
Tomoo
T
Sugawara
Taeko
T
Tarikuz Zaman
A K M
AK
Imagawa
Shogo
S
Dong
Jie
J
Nakai
Yukihito
Y
Mishima
Tetsuya
T
Sobel
Burton E
BE
Kitabatake
Akira
A
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009765:Obesity / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D017395:Plasminogen Activator Inhibitor 1; D011725:Pyridines; D012333:RNA, Messenger; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases