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PMID: 16205723 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Inhibition of RhoA/Rho kinase pathway is involved in the beneficial effect of sildenafil on pulmonary hypertension.

British journal of pharmacology ·Vol. 146 ·No. 7 ·2005-12-00 ·Pages 1010-8

Guilluy C, Sauzeau V, Rolli-Derkinderen M, Guérin P, Sagan C, Pacaud P, Loirand G

Abstract

Inhibition of the type 5 phosphodiesterase and inhibition of Rho kinase are both effective in reducing pulmonary hypertension (PH). Here we investigate whether Rho kinase inhibition is involved in the beneficial effect of the type 5 phosphodiesterase inhibitor sildenafil on PH. Chronic hypoxia-induced PH in rats is associated with an increase in RhoA activity in pulmonary artery that was maximal after 2 days (10.7+/-0.9-fold increase, n=6, P<0.001). The activity of Rho kinase assessed by measuring the level of myosin phosphatase target subunit 1 (MYPT1) phosphorylation was also increased (5.7+/-0.8-fold over control, n=8). Chronic fasudil (30 mg kg(-1) day(-1); 14 days) and sildenafil (25 mg kg(-1) day(-1); 14 days) treatments reduced PH and pulmonary cardiovascular remodelling, and inhibited the MYPT1 phosphorylation in pulmonary artery from hypoxic rats by 82.3+/-3% (n=4) and by 76.6+/-2% (n=4), respectively. The inhibitory effect of sildenafil (10 microM) on MYPT1 phosphorylation was demonstrated by the loss of actin stress fibres in vascular smooth muscle cells. However, in vitro kinase assays indicated that sildenafil had no direct inhibitory action on Rho kinase activity. Sildenafil treatment induced increased RhoA phosphorylation and association to its cytosolic inhibitory protein, guanine dissociation inhibitor (GDI) in pulmonary artery.We propose that sildenafil inhibits RhoA/Rho kinase-dependent functions in pulmonary artery through enhanced RhoA phosphorylation and cytosolic sequestration by GDI. The inhibition of intracellular events downstream of RhoA thus participates in the beneficial effect of sildenafil on PH.

MeSH Terms
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives,therapeutic use Actins/metabolism Animals Carrier Proteins/metabolism Chronic Disease Cytoskeleton/drug effects Guanine Nucleotide Dissociation Inhibitors/physiology Hypertension, Pulmonary/drug therapy,enzymology,etiology Hypoxia/complications Male Phosphodiesterase Inhibitors/pharmacology Phosphoprotein Phosphatases/metabolism Phosphorylation Piperazines/pharmacology,therapeutic use Protein Phosphatase 1 Purines Rats Rats, Wistar Sildenafil Citrate Sulfones rhoA GTP-Binding Protein/antagonists & inhibitors
Chemicals
Actins Carrier Proteins Guanine Nucleotide Dissociation Inhibitors Phosphodiesterase Inhibitors Piperazines Purines Sulfones 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine Sildenafil Citrate Phosphoprotein Phosphatases Ppp1r12a protein, rat Protein Phosphatase 1 rhoA GTP-Binding Protein fasudil
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Guilluy Christophe
INSERM U533, Université de Nantes, Institut du Thorax, Faculté des Sciences, 2 rue de la Houssiniere, BP 92208, 44322 Nantes cedex 3, France.
Sauzeau Vincent
Rolli-Derkinderen Malvyne
Guérin Patrice
Sagan Christine
Pacaud Pierre
Loirand Gervaise
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Article Info
Journal
British journal of pharmacology
Abbr.
Br J Pharmacol
ISSN
0007-1188
DOI
10.1038/sj.bjp.0706408
Published
2005-12-00
Pages
1010-8
Language
English
Region
England
NLM ID
7502536
PMCID
PMC1751229
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.bjp.0706408 PMC Full Text View journal details
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