| Abstract | Pulmonary hypertension (PH) is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells, and migration of inflammatory cells for which no satisfactory treatment has yet been developed. It has been recently demonstrated that Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis and that long-term inhibition of Rho-kinase markedly ameliorates monocrotaline-induced PH in rats. However, it remains to be examined whether direct inhibition of Rho-kinase also ameliorates PH with a different etiology and whether endothelial nitric oxide synthase (eNOS) is involved in the beneficial effects of Rho-kinase inhibition. This study was designed to address those 2 important issues in a hypoxia-induced PH model using wild-type (WT) and eNOS-deficient (eNOS) mice. Long-term blockade of Rho-kinase with fasudil (100 mg/kg/d) for 3 weeks markedly improved PH and right ventricular hypertrophy in WT mice with a lesser but significant inhibition noted in eNOS mice. Fasudil upregulated eNOS with increased Akt phosphorylation in WT but not in eNOS mice. These results suggest that long-term inhibition of Rho-kinase also ameliorates hypoxia-induced PH in mice, for which eNOS activation may partially be involved. |
| Authors | Kohtaro Abe, Shunsuke Tawara, Keiji Oi, Takatoshi Hizume, Toyokazu Uwatoku, Yoshihiro Fukumoto, Kozo Kaibuchi, Hiroaki Shimokawa
(Affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.)
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| Journal | Journal of cardiovascular pharmacology
(J Cardiovasc Pharmacol)
Vol. 48
Issue 6
Pg. 280-5
(Dec 2006)
ISSN: 0160-2446 United States |
| PMID | 17204906
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Intracellular Signaling Peptides and Proteins
- Protein Kinase Inhibitors
- fasudil
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
- Nitric Oxide Synthase Type III
- Proto-Oncogene Proteins c-akt
- Protein-Serine-Threonine Kinases
- rho-Associated Kinases
|
| Topics |
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
(analogs & derivatives, pharmacology, therapeutic use)
- Animals
- Anoxia
(physiopathology)
- Arterioles
(drug effects, physiopathology)
- Blotting, Western
- Disease Models, Animal
- Hypertension, Pulmonary
(physiopathology, prevention & control)
- Hypertrophy, Right Ventricular
(physiopathology, prevention & control)
- Intracellular Signaling Peptides and Proteins
(antagonists & inhibitors, metabolism)
- Lung
(blood supply, drug effects)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Nitric Oxide Synthase Type III
(deficiency, genetics, metabolism)
- Phosphorylation
(drug effects)
- Protein Kinase Inhibitors
(pharmacology, therapeutic use)
- Protein-Serine-Threonine Kinases
(antagonists & inhibitors, metabolism)
- Proto-Oncogene Proteins c-akt
(metabolism)
- Time Factors
- Up-Regulation
(drug effects)
- rho-Associated Kinases
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