Novel signaling pathways contributing to vascular changes in hypertension

Johns, Douglas G.; Dorrance, Anne M.; Leite, Rômulo; Weber, David S.; Webb, R.

doi:10.1007/bf02253359

Cited by 26 publications

(12 citation statements)

References 90 publications

(83 reference statements)

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“…Genistein, daidzein, and glycitein inhibit the growth and DNA synthesis of aortic smooth muscle cells in stroke-prone spontaneously hypertensive rats (Pan et al, 2001). It has been proven recently that activation of the RhoA/Rho-kinase signal transduction pathway is one of the principal mechanisms of vasoconstriction in arterial hypertension and that this pathway is a novel therapeutic target for regulating arterial hypertension (Johns et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

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

Seok¹,

Baek²,

Kim³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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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 F 2␣ (U46619), a thromboxane A2 analog, or KCl 30 min after the pretreatment with genistein (4Ј,5,7-trihydroxyisoflavone), daidzein (4Ј,7-dihydroxyisoflavone), or vehicle. We determined the phosphorylation level of the myosin light chain (MLC 20 ), 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 or KCl increased vascular tension in a concentration-dependent manner, which were inhibited by pretreatment with genistein or daidzein. Both U46619 (30 nM) and KCl (50 mM) increased MLC 20 phosphorylation levels, which were inhibited by genistein and daidzein. Furthermore, both genistein and daidzein decreased the amount of GTP RhoA activated by either U46619 or KCl. U46619 (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.

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Section: Discussionmentioning

confidence: 99%

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

Seok¹,

Baek²,

Kim³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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“…On the other hand, hydrolysis of membrane SM results in generation of ceramide. Recently, ceramide signalling has been considered a novel cell regulatory pathway implicated in the mechanisms for blood pressure control [32]. Thus, if sphingolipid metabolism is enhanced by 2OHOA, then our data will suggest that the net result would be the formation of second messengers and consequently an increased sphingolipid signalling process.…”

Section: Discussionmentioning

confidence: 81%

Effects of 2-hydroxyoleic acid on the structural properties of biological and model plasma membranes

Prades

Alemany

Perona

et al. 2008

Molecular Membrane Biology

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This article maybe used for research, teaching and private study purposes. Any substantial or systematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply or distribution in any form to anyone is expressly forbidden.The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material. AbstractGenetic hypertension is associated with alterations in lipid metabolism, membrane lipid composition and membraneprotein function. 2-Hydroxyoleic acid (2OHOA) is a new antihypertensive molecule that regulates the structure of model membranes and their interaction with certain peripheral signalling proteins in vitro. While the effect of 2OHOA on elevated blood pressure is thought to arise through its influence on signalling proteins, its effects on membrane lipid composition remain to be assessed. 2OHOA administration altered the lipid membrane composition of hypertensive and normotensive rat plasma membranes, and increased the fluidity of reconstituted liver membranes from hypertensive rats. In spontaneously hypertensive rats (SHR), treatment with 2OHOA increased the cholesterol and sphingomyelin content while decreasing that of phosphatidylserine-phosphatidylinositol lipids. In addition, monounsaturated fatty acid levels increased as well as the propensity of reconstituted membranes to form H II -phases. These data suggest that 2OHOA regulates lipid metabolism that is altered in hypertensive animals, and that it affects the structural properties of liver plasma membranes in SHR. These changes in the structural properties of the plasma membrane may modulate the activity of signalling proteins that associate with the cell membrane such as the Gaq/11 protein and hence, signal transduction.

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“…Novel mechanisms involved in alterations of vascular reactivity in isolated vessels have been of great interest to our laboratory (20). The aim of the present study was to evaluate the contribution of the MT network on the vasodilator response induced by histamine, ACh, SNP, and pinacidil in the rat isolated mesenteric arterial bed.…”

Section: Discussionmentioning

confidence: 98%

“…The concentration of the two pharmacological agents used in this study to shift the dynamic state of MTs toward depolymerization, nocodazole and colchicine (10 and 30 M, respectively), were tested previously in different experiments by our group (5,20,26). Considerable published data with immunofluorescence and confocal microscopy techniques have confirmed that concentrations of these agents ranging from 0.5 to 33 M are capable of preventing assembly of tubulin subunits in endothelial and vascular smooth muscle cells after 60-min perfusion of vessels or incubation of cultured cells (22,30,46,50).…”

Section: Discussionmentioning

confidence: 99%

Disruption of microtubular network attenuates histamine-induced dilation in rat mesenteric vessels

Brum

Duarte

Webb³

et al. 2005

American Journal of Physiology-Cell Physiology

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Cytoplasmic microtubules are important in many cellular homeostatic processes in the cell. They regulate cell shape and movement as well as serving as a network by which vesicles and membrane-bound organelles can travel. Lately, there have been many studies demonstrating that microtubules are involved in regulation of intracellular signaling and, therefore, affect vascular reactivity. In this study, we tested the hypothesis that microtubule disruption attenuates agonist-induced endothelium-dependent vasodilation. Isolated mesenteric arterial bed from normotensive rats was preconstricted with phenylephrine, and dose-response curves for histamine, acetylcholine (ACh), sodium nitroprusside (SNP), and pinacidil were performed before and after incubation with nocodazole or colchicine. Treatment of the vascular beds with nocodazole or colchicine significantly attenuated histamine relaxation but did not change the ACh-, SNP-, or pinacidil-induced vasorelaxation. Nocodazole did not cause an additional attenuation of the histamine-mediated dilation in mesenteric vessels in the presence of N -nitro-L-arginine methyl ester, high extracellular K ϩ , or K ϩ channel blockers. These data suggest that disruption of microtubules affects an essential endothelial component of histamine-mediated vasodilation in the mesenteric arterial bed. The mechanism(s) involved in this effect might be related to an impairment of endothelial NO synthesis, which might not be as important for the ACh as for the histamine vasodilator response in rat mesenteric vessels. These results demonstrate the importance of the microtubular system for endothelium-dependent NO-mediated smooth muscle relaxation.nocodazole; nitric oxide; mesenteric arterial bed EUKARYOTIC CELLS CONTAIN a complex set of protein fibers found in the cytoplasm-the cytoskeleton. The cytoskeleton contains three major classes of fibers: actin microfilaments, microtubules (MTs), and intermediate filaments. MTs, a major component of the cytoskeleton, are cylindrical structures composed of two types of protein, ␣-and ␤-tubulin. In general, the biological functions of MTs are partially based on the ability of tubulin to polymerize and depolymerize. In living cells the MTs are in a dynamic process between tubulin dimers and tubulin polymerized into MTs (8).MTs play a role in a variety of cellular functions, including mitosis, trafficking of proteins, shape, and signaling processes (16). In recent years, the role of the MT network in transduction processes in the cell has been the object of several studies. It has been shown that MTs are associated with a variety of proteins involved in cell signaling, including adenylate cyclase (42), phospholipase C (41), and small G proteins (6).The use of various pharmacological agents that affect the polymerization state of the MT network has yielded many novel relationships between MTs and those cell signaling pathways. Nocodazole and colchicine, two destabilizing agents, bind to the colchicine binding site of tubulin, shifting the dynamic state of MTs ...

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Novel signaling pathways contributing to vascular changes in hypertension

Cited by 26 publications

References 90 publications

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

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

Effects of 2-hydroxyoleic acid on the structural properties of biological and model plasma membranes

Disruption of microtubular network attenuates histamine-induced dilation in rat mesenteric vessels

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