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This work reviews a burgeoning body of evidence that RhoA/ROCK signalling is important in the pathogenesis of various experimental models of PH, including chronic hypoxia, monocrotaline, bleomycin, shunt and vascular endothelial growth factor receptor inhibition plus chronic hypoxia-induced PH, and mild hypoxia-induced PH in neonatal fawn-hooded rats. Although information on RhoA/ROCK in human forms of PH is limited, it is also beginning to accumulate, for example see Ref. [60].
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Oka M., Fagan K.A., Jones P.L., and McMurtry I.F. Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension. Br J Pharmacol 155 (2008) 444-454. This work reviews a burgeoning body of evidence that RhoA/ROCK signalling is important in the pathogenesis of various experimental models of PH, including chronic hypoxia, monocrotaline, bleomycin, shunt and vascular endothelial growth factor receptor inhibition plus chronic hypoxia-induced PH, and mild hypoxia-induced PH in neonatal fawn-hooded rats. Although information on RhoA/ROCK in human forms of PH is limited, it is also beginning to accumulate, for example see Ref. [60].
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(2008)
Br J Pharmacol
, vol.155
, pp. 444-454
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Oka, M.1
Fagan, K.A.2
Jones, P.L.3
McMurtry, I.F.4
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49
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57049083665
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Analysis of pulmonary vasodilator responses to the Rho-kinase inhibitor fasudil in the anesthetized rat
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Badejo Jr. A.M., Dhaliwal J.S., Casey D.B., Gallen T.B., Greco A.J., and Kadowitz P.J. Analysis of pulmonary vasodilator responses to the Rho-kinase inhibitor fasudil in the anesthetized rat. Am J Physiol Lung Cell Mol Physiol 295 (2008) L828-L836
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(2008)
Am J Physiol Lung Cell Mol Physiol
, vol.295
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Badejo Jr., A.M.1
Dhaliwal, J.S.2
Casey, D.B.3
Gallen, T.B.4
Greco, A.J.5
Kadowitz, P.J.6
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50
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59249090538
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2+ sensitization
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•]), this strongly implies that superoxide and peroxide have independent effects in PA, which has implications for the ROS hypothesis of HPV, with which this study is otherwise consistent.
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•]), this strongly implies that superoxide and peroxide have independent effects in PA, which has implications for the ROS hypothesis of HPV, with which this study is otherwise consistent.
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(2009)
Free Radic Biol Med
, vol.46
, pp. 633-642
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Knock, G.A.1
Snetkov, V.2
Shaifta, Y.3
Connolly, M.4
Drndarski, S.5
Pourmahram, G.E.6
Aaronson, P.I.7
Ward, J.P.8
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51
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37349071022
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Endothelin-1 and serotonin are involved in activation of RhoA/Rho kinase signaling in the chronically hypoxic hypertensive rat pulmonary circulation
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Homma N., Nagaoka T., Morio Y., Ota H., Gebb S.A., Karoor V., McMurtry I.F., and Oka M. Endothelin-1 and serotonin are involved in activation of RhoA/Rho kinase signaling in the chronically hypoxic hypertensive rat pulmonary circulation. J Cardiovasc Pharmacol 50 (2007) 697-702
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(2007)
J Cardiovasc Pharmacol
, vol.50
, pp. 697-702
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Homma, N.1
Nagaoka, T.2
Morio, Y.3
Ota, H.4
Gebb, S.A.5
Karoor, V.6
McMurtry, I.F.7
Oka, M.8
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52
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33144468890
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2+ and decreased cGMP-induced relaxation
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2+ and decreased cGMP-induced relaxation. Proc Natl Acad Sci U S A 103 (2006) 2440-2445
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(2006)
Proc Natl Acad Sci U S A
, vol.103
, pp. 2440-2445
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Khromov, A.S.1
Wang, H.2
Choudhury, N.3
McDuffie, M.4
Herring, B.P.5
Nakamoto, R.6
Owens, G.K.7
Somlyo, A.P.8
Somlyo, A.V.9
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54
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34147189502
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Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats
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This work demonstrates ROCK-mediated vasoconstriction is a major component of the high PVR in a rat model of severe PH that develops obstructive lesions in small precapillary PA. Whilst ROCK-mediated vasoconstriction continues to be a major factor, the nadir to which right ventricular systolic pressure is reduced by acute ROCK inhibition increases over duration of PH and density of obstructive PA lesions.
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Oka M., Homma N., Taraseviciene-Stewart L., Morris K.G., Kraskauskas D., Burns N., Voelkel N.F., and McMurtry I.F. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res 100 (2007) 923-929. This work demonstrates ROCK-mediated vasoconstriction is a major component of the high PVR in a rat model of severe PH that develops obstructive lesions in small precapillary PA. Whilst ROCK-mediated vasoconstriction continues to be a major factor, the nadir to which right ventricular systolic pressure is reduced by acute ROCK inhibition increases over duration of PH and density of obstructive PA lesions.
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(2007)
Circ Res
, vol.100
, pp. 923-929
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Oka, M.1
Homma, N.2
Taraseviciene-Stewart, L.3
Morris, K.G.4
Kraskauskas, D.5
Burns, N.6
Voelkel, N.F.7
McMurtry, I.F.8
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55
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42049083338
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Chronic hypoxia induces Rho kinase-dependent myogenic tone in small pulmonary arteries
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i and was abolished by ROCK but not PKC inhibition. The mechanism by which chronic hypoxia augments the stretch-induced activation of ROCK is unknown, but this myogenicity likely contributes to the sustained ROCK-dependent vasoconstriction in hypoxic PH.
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i and was abolished by ROCK but not PKC inhibition. The mechanism by which chronic hypoxia augments the stretch-induced activation of ROCK is unknown, but this myogenicity likely contributes to the sustained ROCK-dependent vasoconstriction in hypoxic PH.
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(2008)
Am J Physiol Lung Cell Mol Physiol
, vol.294
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Broughton, B.R.1
Walker, B.R.2
Resta, T.C.3
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57
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33645816773
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Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat
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Nagaoka T., Gebb S.A., Karoor V., Homma N., Morris K.G., McMurtry I.F., and Oka M. Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat. J Appl Physiol 100 (2006) 996-1002
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(2006)
J Appl Physiol
, vol.100
, pp. 996-1002
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Nagaoka, T.1
Gebb, S.A.2
Karoor, V.3
Homma, N.4
Morris, K.G.5
McMurtry, I.F.6
Oka, M.7
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58
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33745155785
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An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension
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Bonnet S., Michelakis E.D., Porter C.J., Andrade-Navarro M.A., Thebaud B., Bonnet S., Haromy A., Harry G., Moudgil R., McMurtry M.S., Weir E.K., et al. An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation 113 (2006) 2630-2641
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(2006)
Circulation
, vol.113
, pp. 2630-2641
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Bonnet, S.1
Michelakis, E.D.2
Porter, C.J.3
Andrade-Navarro, M.A.4
Thebaud, B.5
Bonnet, S.6
Haromy, A.7
Harry, G.8
Moudgil, R.9
McMurtry, M.S.10
Weir, E.K.11
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59
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53849083055
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Novel interactions between the 5-HT transporter, 5-HT1B receptors and Rho kinase in vivo and in pulmonary fibroblasts
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Mair K.M., MacLean M.R., Morecroft I., Dempsie Y., and Palmer T.M. Novel interactions between the 5-HT transporter, 5-HT1B receptors and Rho kinase in vivo and in pulmonary fibroblasts. Br J Pharmacol 155 (2008) 606-616
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(2008)
Br J Pharmacol
, vol.155
, pp. 606-616
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Mair, K.M.1
MacLean, M.R.2
Morecroft, I.3
Dempsie, Y.4
Palmer, T.M.5
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60
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58149242457
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Dexfenfluramine discontinuous treatment does not worsen hypoxia-induced pulmonary vascular remodeling but activates RhoA/ROCK pathway: consequences on pulmonary hypertension
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Desbuards N., Antier D., Rochefort G.Y., Apfeldorfer C.S., Schenck E., Hanton G., and Hyvelin J.M. Dexfenfluramine discontinuous treatment does not worsen hypoxia-induced pulmonary vascular remodeling but activates RhoA/ROCK pathway: consequences on pulmonary hypertension. Eur J Pharmacol 602 (2009) 355-363
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(2009)
Eur J Pharmacol
, vol.602
, pp. 355-363
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Desbuards, N.1
Antier, D.2
Rochefort, G.Y.3
Apfeldorfer, C.S.4
Schenck, E.5
Hanton, G.6
Hyvelin, J.M.7
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61
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66049144587
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The non-canonical WNT-pathway is operative in idiopathic pulmonary arterial hypertension
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This study found upregulation in IPAH PA of several mediators of the canonical and non-canonical, the planar cell polarity, WNT pathways, the latter of which included wingless member 11, disheveled associated activator of morphogenesis-1, disheveled, Rac1, RhoA and ROCK. Immunohistochemical staining confirmed the enhanced expression of the planar cell polarity pathway mediators in both large and small PA. Functional studies are required to identify the contributions of the canonical and non-canonical WNT pathways to the pathogenesis of IPAH. At least two other reports of increased RhoA/ROCK activity in human hypertensive PA are currently under review.
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Laumanns I.P., Fink L., Wilhelm J., Wolff J.C., Mitnacht-Kraus R., Graef-Hoechst S., Stein M.M., Bohle R.M., Klepetko W., Hoda M.A.R., Schermuly R.T., et al. The non-canonical WNT-pathway is operative in idiopathic pulmonary arterial hypertension. Am J Respir Cell Mol Biol 40 (2009) 683-691. This study found upregulation in IPAH PA of several mediators of the canonical and non-canonical, the planar cell polarity, WNT pathways, the latter of which included wingless member 11, disheveled associated activator of morphogenesis-1, disheveled, Rac1, RhoA and ROCK. Immunohistochemical staining confirmed the enhanced expression of the planar cell polarity pathway mediators in both large and small PA. Functional studies are required to identify the contributions of the canonical and non-canonical WNT pathways to the pathogenesis of IPAH. At least two other reports of increased RhoA/ROCK activity in human hypertensive PA are currently under review.
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(2009)
Am J Respir Cell Mol Biol
, vol.40
, pp. 683-691
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Laumanns, I.P.1
Fink, L.2
Wilhelm, J.3
Wolff, J.C.4
Mitnacht-Kraus, R.5
Graef-Hoechst, S.6
Stein, M.M.7
Bohle, R.M.8
Klepetko, W.9
Hoda, M.A.R.10
Schermuly, R.T.11
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