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

Biosci Biotechnol Biochem. 2019 Jun;83(6):1000-1010. doi: 10.1080/09168451.2019.1584520. Epub 2019 Mar 5.

Abstract

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.

Keywords: cAMP; cGMP; rat model of monocrotaline-induced pulmonary hypertension.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cells, Cultured
  • Collagen Type I / metabolism
  • Collagen Type I, alpha 1 Chain
  • 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*
  • Rats, Wistar
  • Transforming Growth Factor beta / physiology

Substances

  • Bdnf protein, rat
  • Brain-Derived Neurotrophic Factor
  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Fibronectins
  • Phosphodiesterase 5 Inhibitors
  • Transforming Growth Factor beta
  • Monocrotaline
  • Cyclic AMP
  • Cyclic GMP