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CARDIOVASCULAR

Isoflavone Attenuates Vascular Contraction through Inhibition of the RhoA/Rho-Kinase Signaling Pathway

Department of Pharmacology (Y.M.S., I.B., I.K.K.), Cardiovascular Research Institute (I.K.K.), Kyungpook National University School of Medicine, Daegu, Republic of Korea; and Department of Biochemistry, College of Natural Sciences (Y.-H.K.), Division of Plant Biosciences, College of Agriculture and Life Sciences (Y.-S.J., I.-J.L., D.H.S., Y.H.H.), Kyungpook National University, Daegu, Republic of Korea

Isoflavones decrease blood pressure, improve lipid profiles, and restore vascular function. We hypothesized that isoflavone attenuates vascular contraction by inhibiting RhoA/Rho-kinase signaling pathway. Rat aortic rings were denuded of endothelium, mounted in organ baths, and contracted with 11,9 epoxymethano-prostaglandin F₂ (U46619 [GenBank] ), a thromboxane A2 analog, or KCl 30 min after the pretreatment with genistein (4',5,7-trihydroxyisoflavone), daidzein (4',7-dihydroxyisoflavone), or vehicle. We determined the phosphorylation level of the myosin light chain (MLC₂₀), myosin phosphatase-targeting subunit 1 (MYPT1), and protein kinase C-potentiated inhibitory protein for heterotrimeric myosin light-chain phosphatase of 17 kDa (CPI17) by means of the Western blot. We also measured the amount of GTP RhoA as a marker regarding RhoA activation. The cumulative additions of U46619 [GenBank] or KCl increased vascular tension in a concentration-dependent manner, which were inhibited by pretreatment with genistein or daidzein. Both U46619 [GenBank] (30 nM) and KCl (50 mM) increased MLC₂₀ phosphorylation levels, which were inhibited by genistein and daidzein. Furthermore, both genistein and daidzein decreased the amount of GTP RhoA activated by either U46619 [GenBank] or KCl. U46619 [GenBank] (30 nM) increased phosphorylation of the MYPT1_Thr855 and CPI17_Thr38, which were also inhibited by genistein or daidzein. However, neither genistein nor daidzein inhibited phorbol 12,13-dibutyrate-induced vascular contraction and CPI17 phosphorylation. In conclusion, isoflavone attenuates vascular contraction, at least in part, through inhibition of the RhoA/Rho-kinase signaling pathway.

Address correspondence to: Dr. In Kyeom Kim, Department of Pharmacology, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea. E-mail: inkim{at}knu.ac.kr