Improvement of pulmonary arterial hypertension, inflammatory response, and epithelium injury by dual activation of cAMP/cGMP pathway in a rat model of monocrotaline-induced pulmonary hypertension

Pulmonary hypertension (PH) is a life-threatening lung disease. PH with concomitant lung diseases, e.g., idiopathic pulmonary fibrosis, is associated with poor prognosis. Development of novel therapeutic vasodilators for treatment of these patients is a key imperative. We evaluated the efficacy of d...

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Bibliographic Details
Published in:Bioscience, biotechnology, and biochemistry biotechnology, and biochemistry, 2019-06, Vol.83 (6), p.1000-1010
Main Authors: Muraki, Yo, Naito, Takako, Tohyama, Kimio, Shibata, Sachio, Kuniyeda, Kanako, Nio, Yasunori, Hazama, Masatoshi, Matsuo, Takanori
Format: Article
Language:English
Subjects:
Animals
Brain-Derived Neurotrophic Factor - metabolism
cAMP
Cells, Cultured
cGMP
Collagen Type I - metabolism
Cyclic AMP - metabolism
Cyclic GMP - metabolism
Disease Models, Animal
Epithelium - injuries
Fibronectins - metabolism
Gene Expression Regulation - drug effects
Gene Expression Regulation - physiology
Humans
Hypertension, Pulmonary - chemically induced
Hypertension, Pulmonary - drug therapy
Inflammation - therapy
Lung - drug effects
Lung - metabolism
Lung - pathology
Monocrotaline - toxicity
Phosphodiesterase 5 Inhibitors - pharmacology
Phosphodiesterase 5 Inhibitors - therapeutic use
rat model of monocrotaline-induced pulmonary hypertension
Rats, Wistar
Transforming Growth Factor beta - physiology
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Summary:Pulmonary hypertension (PH) is a life-threatening lung disease. PH with concomitant lung diseases, e.g., idiopathic pulmonary fibrosis, is associated with poor prognosis. Development of novel therapeutic vasodilators for treatment of these patients is a key imperative. We evaluated the efficacy of dual activation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) using an active, small-molecule phosphodiesterase (PDE4)/PDE5 dual inhibitor (Compound A). Compound A increased both cAMP and cGMP levels in WI-38 lung fibroblasts and suppressed the expressions of type-1 collagen α1 chain and fibronectin. Additionally, compound A reduced right ventricular weight/left ventricular weight+septal weight ratio, brain natriuretic peptide expression levels in right ventricle, C─C motif chemokine ligand 2 expression levels in lung, and plasma surfactant protein D. Our data indicate that dual activation of cAMP/cGMP pathways may be a novel treatment strategy for PH. Elevated cAMP suppresses profibrotic and inflammatory responses. Elevated cGMP enhances vasodilation and suppresses proliferation of smooth muscle cells.
ISSN:0916-8451
1347-6947
DOI:10.1080/09168451.2019.1584520