title: A novel ACE2 activator reduces monocrotaline-induced pulmonary hypertension by suppressing the JAK/STAT and TGF-β cascades with restored caveolin-1 expression.
abstract: BACKGROUND
  Pulmonary hypertension (PH) is characterized by increased pressure in the pulmonary artery and right ventricular hypertrophy (RVH). Recently, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), was shown to inhibit experimental PH. Here we identified a novel ACE2 activator and investigated how the compound reduced monocrotaline (MCT)-induced PH.
  
  
  METHODS
  To induce PH, Sprague-Dawley rats were injected subcutaneously with MCT, followed by the continuous administration of NCP-2454, an ACE2 activator, using osmotic pumps. Pulmonary arterial compliance was monitored every week until 4 weeks post-injection (wpi). RVH and lung remodeling was evaluated using lung tissue at 4 wpi.
  
  
  RESULTS
  NCP-2454 upregulated the production of Ang-(1-7) when incubated with ACE2 and Ang II. Notably, a continuous infusion of NCP-2454 significantly improved pulmonary arterial compliance, right ventricular systolic pressure, and RVH in MCT-treated rats. Interestingly, NCP-2454 increased the relative expression of ACE2 and MAS mRNA in lung tissue, especially in MCT-treated rats. In addition, the compound inhibited the MCT-induced overexpression of transforming growth factor β, phosphorylation of signal transducer and activator of transcription-3 (STAT3), and interleukin-6 production. The compound also restored the expression of caveolin-1 (Cav-1), which negatively regulates the Janus kinase-STAT signaling cascade.
  
  
  CONCLUSIONS
  NCP-2454 prevented MCT-induced PH by suppressing intracellular inflammatory cascades, an upstream molecular change of which is the disruption of Cav-1 expression.
authors.affiliation: 1Department of Intractable Diseases, Institute of National Center for Global Health and Medicine , Tokyo , Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Haga
authors.forename: Haruka
authors.initials: H
authors.lastname: Tsuchiya
authors.forename: Toshitake
authors.initials: T
authors.lastname: Hirai
authors.forename: Takaichi
authors.initials: T
authors.lastname: Hamano
authors.forename: Akio
authors.initials: A
authors.lastname: Mimori
authors.forename: Yukihito
authors.initials: Y
authors.lastname: Ishizaka
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D025461:Feedback, Physiological / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000517:prevention & control; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D016686:Monocrotaline; D010080:Oxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D050791:STAT Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D051242:Caveolin 1; C000601996:NCP-2454; D010080:Oxazoles; D011743:Pyrimidines; D050791:STAT Transcription Factors; D016212:Transforming Growth Factor beta; D016686:Monocrotaline; D053612:Janus Kinases; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2
keywords: ACE2 activator; Caveolin-1; monocrotaline; pulmonary hypertension