Roles of Rho/Rho-kinase signaling in hypertension and pulmonary hypertension

Background- The complex and multifactorial pathogenesis of pulmonary hypertension (PH) involves constriction, remodeling, and in situ thrombosis of pulmonary vessels. Both serotonin (5-HT) and Rho kinase signaling may contribute to these alterations. Here, we investigated possible links between the 5-HT transporter (5-HTT) and RhoA/Rho kinase pathways, as well as their involvement in the progression of human and experimental PH. Methods and Results- Lungs, platelets, and quiescent cultured pulmonary-artery smooth-muscle cells (PA-SMCs) from patients with idiopathic PH (iPH) were characterized by marked elevations in RhoA and Rho kinase activity and by a strong increase in serotonin binding to RhoA, compared to controls. The 5-HTT inhibitor fluoxetine and the type 2 transglutaminase inhibitor monodansylcadaverin prevented 5-HT-induced RhoA serotonylation and RhoA/Rho kinase activation, as well as 5-HT-induced proliferation of PA-SMCs from iPH patients, that was also inhibited by the Rho kinase inhibitor fasudil. Increased Rho kinase activity, RhoA activation, and RhoA serotonylation were also observed in lungs from SM22–5-HTT+ mice, which overexpress 5-HTT in smooth muscle and spontaneously develop PH. Treatment of SM22–5-HTT+ mice with either fasudil or fluoxetine limited both PH progression and RhoA/Rho kinase activation. Conclusions- RhoA and Rho kinase activities are increased in iPH, as a result of transglutaminase-mediated transamidation of RhoA by 5-HT internalized via 5-HTT. Direct involvement of this pathway in 5-HT-mediated PA-SMC proliferation and platelet activation during PH progression identify RhoA/Rho kinase signaling as a promising target for new treatments against PH.

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RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertension

Vascular Health and Risk Management ◽

10.2147/vhrm.s4711 ◽

2009 ◽

pp. 663 ◽

Cited By ~ 37

Author(s):

Scott Barman

Keyword(s):

Pulmonary Hypertension ◽

Therapeutic Target ◽

Rho Kinase ◽

Kinase Signaling

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Statins may ameliorate pulmonary hypertension via RhoA/Rho-kinase signaling pathway

Medical Hypotheses ◽

10.1016/j.mehy.2006.09.034 ◽

2007 ◽

Vol 68 (5) ◽

pp. 1108-1113 ◽

Cited By ~ 17

Author(s):

Xi-Qian Xing ◽

Ye Gan ◽

Shang-Jie Wu ◽

Ping Chen ◽

Rui Zhou ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Signaling Pathway ◽

Rho Kinase ◽

Kinase Signaling ◽

Kinase Signaling Pathway

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Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat

Journal of Applied Physiology ◽

10.1152/japplphysiol.01028.2005 ◽

2006 ◽

Vol 100 (3) ◽

pp. 996-1002 ◽

Cited By ~ 81

Author(s):

Tetsutaro Nagaoka ◽

Sarah A. Gebb ◽

Vijaya Karoor ◽

Noriyuki Homma ◽

Kenneth G. Morris ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Sea Level ◽

Kinase Inhibitor ◽

Pulmonary Arteries ◽

Rho Kinase ◽

Kinase Signaling ◽

Rhoa Activity ◽

Pulmonary Arterial ◽

Mild Hypoxia

The fawn-hooded rat (FHR) develops severe pulmonary hypertension (PH) when raised for the first 3–4 wk of life in the mild hypoxia of Denver’s altitude (5,280 ft.). The PH is associated with sustained pulmonary vasoconstriction and pulmonary artery remodeling. Furthermore, lung alveolarization and vascularization are reduced in the Denver FHR. We have recently shown that RhoA/Rho kinase signaling is involved in both vasoconstriction and vascular remodeling in animal models of hypoxic PH. In this study, we investigated the role of RhoA/Rho kinase signaling in the PH of Denver FHR. In α-toxin permeabilized pulmonary arteries from Denver FHR, the contractile sensitivity to Ca2+was increased compared with those from sea-level FHR. RhoA activity and Rho kinase I protein expression in pulmonary arteries of Denver FHR (10-wk-old) were higher than in those of sea-level FHR. Acute inhalation of the Rho kinase inhibitor fasudil selectively reduced the elevated pulmonary arterial pressure in Denver FHR in vivo. Chronic fasudil treatment (30 mg·kg−1·day−1, from birth to 10 wk old) markedly reduced the development of PH and improved lung alveolarization and vascularization in Denver FHR. These results suggest that Rho kinase-mediated sustained vasoconstriction, through increased Ca2+sensitivity, plays an important role in the established PH and that RhoA/Rho kinase signaling contributes significantly to the development of PH and lung dysplasia in mild hypoxia-exposed FHR.

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Faculty Opinions recommendation of RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1163096.623755 ◽

2009 ◽

Author(s):

Ivan McMurtry ◽

Masahiko Oka

Keyword(s):

Pulmonary Hypertension ◽

Rho Kinase ◽

Kinase Activation

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877 ATTENUATED RHOA/RHO-KINASE SIGNALING IN THE PENIS OF TRANSGENIC SICKLE CELL MICE

The Journal of Urology ◽

10.1016/j.juro.2010.02.1633 ◽

2010 ◽

Vol 183 (4S) ◽

Cited By ~ 1

Author(s):

Trinity Bivalacqua ◽

Ashley Ross ◽

Travis Strong ◽

Milena Gebska ◽

Blijana Musicki ◽

...

Keyword(s):

Sickle Cell ◽

Rho Kinase ◽

Kinase Signaling

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The atypical structure and function of newborn arterial endothelium is mediated by Rho/Rho kinase signaling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00327.2014 ◽

2014 ◽

Vol 307 (4) ◽

pp. H628-H632 ◽

Cited By ~ 10

Author(s):

Sheila Flavahan ◽

Nicholas A. Flavahan

Keyword(s):

Laser Scanning ◽

Rho Kinase ◽

Laser Scanning Microscopy ◽

Scanning Microscopy ◽

Stress Fibers ◽

Light Chains ◽

Myosin Light Chains ◽

Kinase Signaling ◽

No Donor ◽

Kinase Inhibition

Endothelium of fetal or newborn arteries is atypical, displaying actin stress fibers and reduced nitric oxide (NO)-mediated dilatation. This study tested the hypothesis that Rho/Rho kinase signaling, which promotes endothelial stress fibers and inhibits endothelial dilatation, contributed to this phenotype. Carotid arteries were isolated from newborn [ postnatal day 1 (P1)], P7, and P21 mice. Endothelial dilatation to acetylcholine (pressure myograph) was minimal at P1, increased at P7, and further increased at P21. Inhibition of Rho (C3 transferase) or Rho kinase (Y27632, fasudil) significantly increased dilatation to acetylcholine in P1 arteries but had no effect in P7 or P21 arteries. After inhibition of NO synthase ( NG-nitro-l-arginine methyl ester), Rho kinase inhibition no longer increased acetylcholine responses in P1 arteries. Rho kinase inhibition did not affect dilatation to the NO donor DEA-NONOate. The endothelial actin cytoskeleton was labeled with phalloidin and visualized by laser-scanning microscopy. In P1 arteries, the endothelium had prominent transcytoplasmic stress fibers, whereas in P7 and P21 arteries, the actin fibers had a significantly reduced intensity and were restricted to cell borders. Phosphorylation of myosin light chains, a Rho kinase substrate, was highest in P1 endothelium and significantly reduced in P7 and P21 endothelium (laser-scanning microscopy). In P1 arteries, inhibition of Rho (C3 transferase) or Rho kinase (Y27632) significantly reduced the intensity of actin fibers, which were restricted to cell borders. Similarly, in P1 arteries, Rho inhibition significantly reduced endothelial levels of phosphorylated myosin light chains. These results indicate that the atypical function and morphology of newborn endothelium is mediated by Rho/Rho kinase signaling.

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