Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension

Frances S de Man, Ly Tu, M Louis Handoko, Silvia Rain, Gerrina Ruiter, Charlène François, Ingrid Schalij, Peter Dorfmüller, Gérald Simonneau, Elie Fadel, Frederic Perros, Anco Boonstra, Piet E Postmus, Jolanda van der Velden, Anton Vonk-Noordegraaf, Marc Humbert, Saadia Eddahibi, Christophe Guignabert

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

RATIONALE: 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.

OBJECTIVES: 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.

MEASUREMENTS AND MAIN 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.

Original languageEnglish
Pages (from-to)780-9
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume186
Issue number8
DOIs
Publication statusPublished - 15 Oct 2012
Externally publishedYes

Keywords

  • Angiotensin II Type 1 Receptor Blockers/pharmacology
  • Animals
  • Case-Control Studies
  • Cells, Cultured
  • Disease Progression
  • Endothelium, Vascular
  • Familial Primary Pulmonary Hypertension
  • Female
  • Humans
  • Hypertension, Pulmonary/drug therapy
  • Losartan/pharmacology
  • Male
  • Middle Aged
  • Monocrotaline
  • Myocytes, Smooth Muscle
  • Proportional Hazards Models
  • Rats
  • Receptor, Angiotensin, Type 1/metabolism
  • Renin-Angiotensin System/drug effects
  • Up-Regulation

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