Back to Search
Start Over
Dysregulated Renin-Angiotensin-Aldosterone System Contributes to Pulmonary Arterial Hypertension
- Source :
- American Journal of Respiratory and Critical Care Medicine, 186(8), 780-789. American Thoracic Society, American Journal of Respiratory and Critical Care Medicine, American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, 2012, 186 (8), pp.780-9. ⟨10.1164/rccm.201203-0411OC⟩, de Man, F S, Tu, L, Handoko, M L, Rain, S, Ruiter, G, Francois, C, Schalij, I, Dorfmuller, P, Simonneau, G, Fadel, E, Perros, F, Boonstra, A, Postmus, P E, van der Velden, J, Vonk Noordegraaf, A, Humbert, M, Eddahibi, S & Guignabert, C 2012, ' Dysregulated Renin-Angiotensin-Aldosterone System Contributes to Pulmonary Arterial Hypertension ', American Journal of Respiratory and Critical Care Medicine, vol. 186, no. 8, pp. 780-789 . https://doi.org/10.1164/rccm.201203-0411OC
- Publication Year :
- 2012
-
Abstract
- International audience; 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.
- Subjects :
- Sympathetic nervous system
Cardiac output
medicine.medical_treatment
030204 cardiovascular system & hematology
Critical Care and Intensive Care Medicine
MESH: Monocrotaline
MESH: Proportional Hazards Models
0302 clinical medicine
MESH: Renin-Angiotensin System
idiopathic pulmonary arterial hypertension
MESH: Up-Regulation
MESH: Losartan
MESH: Animals
renin angiotensin system
MESH: Middle Aged
MESH: Myocytes, Smooth Muscle
monocrotaline
MESH: Case-Control Studies
endothelial cells
3. Good health
smooth muscle cells
medicine.anatomical_structure
Losartan
MESH: Receptor, Angiotensin, Type 1
Cardiology
MESH: Disease Progression
MESH: Endothelium, Vascular
medicine.drug
MESH: Cells, Cultured
Pulmonary and Respiratory Medicine
medicine.medical_specialty
MESH: Rats
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
03 medical and health sciences
Pneumonectomy
Internal medicine
Renin–angiotensin system
medicine
Lung transplantation
Lung
MESH: Humans
MESH: Hypertension, Pulmonary
business.industry
MESH: Angiotensin II Type 1 Receptor Blockers
medicine.disease
Pulmonary hypertension
MESH: Male
030228 respiratory system
business
MESH: Female
Subjects
Details
- ISSN :
- 1073449X and 15354970
- Database :
- OpenAIRE
- Journal :
- American Journal of Respiratory and Critical Care Medicine, 186(8), 780-789. American Thoracic Society, American Journal of Respiratory and Critical Care Medicine, American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, 2012, 186 (8), pp.780-9. ⟨10.1164/rccm.201203-0411OC⟩, de Man, F S, Tu, L, Handoko, M L, Rain, S, Ruiter, G, Francois, C, Schalij, I, Dorfmuller, P, Simonneau, G, Fadel, E, Perros, F, Boonstra, A, Postmus, P E, van der Velden, J, Vonk Noordegraaf, A, Humbert, M, Eddahibi, S & Guignabert, C 2012, ' Dysregulated Renin-Angiotensin-Aldosterone System Contributes to Pulmonary Arterial Hypertension ', American Journal of Respiratory and Critical Care Medicine, vol. 186, no. 8, pp. 780-789 . https://doi.org/10.1164/rccm.201203-0411OC
- Accession number :
- edsair.doi.dedup.....cec9503c2a2659111ebbdbf89a53f675