title: Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension.
abstract: BACKGROUND
  Patients with idiopathic pulmonary arterial hypertension (iPAH) often have a low cardiac output. To compensate, neurohormonal systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system are up-regulated, but this may have long-term negative effects on the progression of iPAH.
  
  
  OBJECTIVE
  Assess systemic and pulmonary RAAS activity in patients with iPAH and determine the efficacy of chronic RAAS inhibition in experimental PAH.
  
  
  METHODS
  We collected 79 blood samples from 58 patients with iPAH in the VU University Medical Center Amsterdam (between 2004 and 2010) to determine systemic RAAS activity.
  
  
  RESULTS
  We observed increased levels of renin, angiotensin (Ang)I, and AngII, which were associated with disease progression (P < 0.05) and mortality (P < 0.05). To determine pulmonary RAAS activity, lung specimens were obtained from patients with iPAH (during lung transplantation, n = 13) and control subjects (during lobectomy or pneumonectomy for cancer, n = 14). Local RAAS activity in pulmonary arteries of patients with iPAH was increased, demonstrated by elevated angiotensin-converting enzyme activity in pulmonary endothelial cells and increased AngII type 1 (AT(1)) receptor expression and signaling. In addition, local RAAS up-regulation was associated with increased pulmonary artery smooth muscle cell proliferation via enhanced AT(1) receptor signaling in patients with iPAH compared with control subjects. Finally, to determine the therapeutic potential of RAAS activity, we assessed the chronic effects of an AT(1) receptor antagonist (losartan) in the monocrotaline PAH rat model (60 mg/kg). Losartan delayed disease progression, decreased right ventricular afterload and pulmonary vascular remodeling, and restored right ventricular-arterial coupling in rats with PAH.
  
  
  CONCLUSIONS
  Systemic and pulmonary RAAS activities are increased in patients with iPAH and are associated with increased pulmonary vascular remodeling. Chronic inhibition of RAAS by losartan is beneficial in experimental PAH.
authors.affiliation: VU University Medical Center, Department of Pulmonology, De Boelelaan 1117, Amsterdam, The Netherlands. fs.deman@vumc.nl
authors.forename: Frances S
authors.initials: FS
authors.lastname: de Man
authors.forename: Ly
authors.initials: L
authors.lastname: Tu
authors.forename: M Louis
authors.initials: ML
authors.lastname: Handoko
authors.forename: Silvia
authors.initials: S
authors.lastname: Rain
authors.forename: Gerrina
authors.initials: G
authors.lastname: Ruiter
authors.forename: Charlène
authors.initials: C
authors.lastname: François
authors.forename: Ingrid
authors.initials: I
authors.lastname: Schalij
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmüller
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.forename: Frederic
authors.initials: F
authors.lastname: Perros
authors.forename: Anco
authors.initials: A
authors.lastname: Boonstra
authors.forename: Piet E
authors.initials: PE
authors.lastname: Postmus
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
authors.forename: Anton
authors.initials: A
authors.lastname: Vonk-Noordegraaf
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.forename: Saadia
authors.initials: S
authors.lastname: Eddahibi
authors.forename: Christophe
authors.initials: C
authors.lastname: Guignabert
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D018450:Disease Progression; D004730:Endothelium, Vascular; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D016686:Monocrotaline; D032389:Myocytes, Smooth Muscle; D016016:Proportional Hazards Models; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D016686:Monocrotaline; D019808:Losartan