Rho/Rho-kinase Signaling in Hypoxic Pulmonary Hypertension

The 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor, simvastatin, has been shown to attenuate chronic hypoxic pulmonary hypertension (CHPH). Here, we assess whether simvastatin is capable of inducing regression of established CHPH and explore potential mechanisms of statin effect. Rats ( n = 8 in each group) were exposed to chronic hypoxia (10% FiO2) for 2 or 4 wk. Simvastatin treatment (20 mg·kg−1·day−1) commenced after 2 wk of hypoxia, at which time CHPH was fully established, reduced mean pulmonary artery pressure (19 ± 0.5 vs. 27 ± 0.9 mmHg; P < 0.001), the ratio of right ventricular free wall to left ventricular plus septal weight (0.41 ± 0.03 vs. 0.54 ± 0.03; P < 0.001), and medial thickening of small pulmonary arteries (13 ± 0.4 vs. 16 ± 0.4%; P < 0.01) compared with 4-wk hypoxic controls. Supplementation with mevalonate (50 mg·kg−1·day−1) prevented the attenuation of CHPH induced by simvastatin during 2 wk of hypoxia. Because statins are known to inhibit Rho-kinase (ROCK), we determined expression of ROCK-1 and -2 in whole lung by Western blot and ROCK activity by phosphorylation of the myosin-binding subunit of myosin phosphatase. Expression of both ROCK-1 and -2 were markedly diminished in simvastatin-treated animals during normoxia and hypoxia (2- and 4-wk) exposure ( P < 0.01). ROCK activity was increased threefold under hypoxic conditions and normalized with simvastatin treatment ( P < 0.001). We conclude that simvastatin attenuates and induces regression of established CHPH through inhibition of HMG-CoA reductase. Inhibition of ROCK expression and activity may be an important mechanism of statin effect.

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Sustained therapeutic hypercapnia attenuates pulmonary arterial Rho-kinase activity and ameliorates chronic hypoxic pulmonary hypertension in juvenile rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01180.2011 ◽

2012 ◽

Vol 302 (12) ◽

pp. H2599-H2611 ◽

Cited By ~ 18

Author(s):

Gary Peng ◽

Julijana Ivanovska ◽

Crystal Kantores ◽

Todd Van Vliet ◽

Doreen Engelberts ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Smooth Muscle ◽

Right Ventricular ◽

Rho Kinase ◽

Juvenile Rats ◽

Hypoxic Pulmonary Hypertension ◽

Rescue Treatment ◽

Pulmonary Arterial ◽

Rock Activity

Sustained therapeutic hypercapnia prevents pulmonary hypertension in experimental animals, but its rescue effects on established disease have not been studied. Therapies that inhibit Rho-kinase (ROCK) and/or augment nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling can reverse or prevent progression of chronic pulmonary hypertension. Our objective in the present study was to determine whether sustained rescue treatment with inhaled CO2 (therapeutic hypercapnia) would improve structural and functional changes of chronic hypoxic pulmonary hypertension. Spontaneously breathing pups were exposed to normoxia (21% O2) or hypoxia (13% O2) from postnatal days 1–21 with or without 7% CO2 (PaCO2 elevated by ∼25 mmHg) or 10% CO2 (PaCO2 elevated by ∼40 mmHg) from days 14 to 21. Compared with hypoxia alone, animals exposed to hypoxia and 10% CO2 had significantly ( P < 0.05) decreased pulmonary vascular resistance, right-ventricular systolic pressure, right-ventricular hypertrophy, and medial wall thickness of pulmonary resistance arteries as well as decreased lung phosphodiesterase (PDE) V, RhoA, and ROCK activity. Rescue treatment with 10% CO2, or treatment with a ROCK inhibitor (15 mg/kg ip Y-27632 twice daily from days 14 to 21), also increased pulmonary arterial endothelial nitric oxide synthase and lung NO content. In contrast, cGMP content and cGMP-dependent protein kinase (PKG) activity were increased by exposure to 10% CO2, but not by ROCK inhibition with Y-27632. In vitro exposure of pulmonary artery smooth muscle cells to hypercapnia suppressed serum-induced ROCK activity, which was prevented by inhibition of PKG with Rp-8-Br-PET-cGMPS. We conclude that sustained hypercapnia dose-dependently inhibited ROCK activity, augmented NO-cGMP-PKG signaling, and led to partial improvements in the hemodynamic and structural abnormalities of chronic hypoxic PHT in juvenile rats. Increased PKG content and activity appears to play a major upstream role in CO2-induced suppression of ROCK activity in pulmonary arterial smooth muscle.

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Attenuation of Acute Hypoxic Pulmonary Vasoconstriction and Hypoxic Pulmonary Hypertension in Mice by Inhibition of Rho-kinase

Yearbook of Pulmonary Disease ◽

10.1016/s8756-3452(08)70137-3 ◽

2006 ◽

Vol 2006 ◽

pp. 172-177

Keyword(s):

Pulmonary Hypertension ◽

Hypoxic Pulmonary Vasoconstriction ◽

Rho Kinase ◽

Hypoxic Pulmonary Hypertension ◽

Pulmonary Vasoconstriction

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Structural Narrowing Of The Vascular Lumen Is The Major Mechanism Underlying Chronic Hypoxic Pulmonary Hypertension In The Mouse, Not Rho Kinase Dependent Vasoconstriction

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a2628 ◽

2012 ◽

Author(s):

S C. Rowan ◽

E Cahill ◽

M Sands ◽

M Banahan ◽

D Ryan ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Rho Kinase ◽

Hypoxic Pulmonary Hypertension ◽

Major Mechanism ◽

Vascular Lumen

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Abstract 1633: RhoA and Rho Kinase Activation in Human Pulmonary Hypertension - Role of 5-HT Signaling

Circulation ◽

10.1161/circ.118.suppl_18.s_361-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Christophe Guilluy ◽

Saadia Eddahibi ◽

Christian Agard ◽

Laurent Savale ◽

Elie Fadel ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Kinase Activity ◽

Kinase Inhibitor ◽

Rho Kinase ◽

Strong Increase ◽

Kinase Signaling ◽

Kinase Activation ◽

Promising Target ◽

New Treatments

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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