Intracellular signal transduction modulating expression of plasminogen activator inhibitor-1 in adipocytes

• Published in: Biochemical pharmacology 2003-06, Vol.65 (11), p.1907-1914
• Main Authors: Goto, Daisuke, Fujii, Satoshi, Kaneko, Takeaki, Furumoto, Tomoo, Sugawara, Taeko, Tarikuz Zaman, A.K.M., Imagawa, Shogo, Dong, Jie, Nakai, Yukihito, Mishima, Tetsuya, Sobel, Burton E., Kitabatake, Akira
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Adipocyte; Adipocytes - drug effects; Adipocytes - metabolism; Amides - pharmacology; Animals; Biological and medical sciences; Enzyme Inhibitors - pharmacology; Fibrinolysis; Flavonoid; Intracellular Signaling Peptides and Proteins; Medical sciences; Mice; Obesity; Obesity - metabolism; Plasminogen Activator Inhibitor 1 - biosynthesis; Plasminogen Activator Inhibitor 1 - genetics; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Pyridines - pharmacology; rho-Associated Kinases; Rho-kinase; RNA, Messenger - biosynthesis; Signal Transduction - drug effects; Signal Transduction - physiology; Thrombosis
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(03)00162-X

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-β (TGF-β) expression in chicken embryonic heart cells. Because TGF-β 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.