Rationale: Patients with idiopathic pulmonary arterial hypertension (iPAH) often have a low cardiac output. To compensate, neuro-hormonal systems like renin-angiotensin-aldosteron system (RAAS) and sympathetic nervous system can be upregulated. Although its initial compensatory effects, long-term neuro-hormonal activity can be detrimental.Objectives
1. Is systemic and local RAAS-activity increased in iPAH-patients?Objectives
2. Can local RAAS-activity induce pulmonary artery smooth muscle cell (PA-SMC) proliferation?Objectives
3. Is RAAS-activity a potential therapeutic target for PAH?Findings
Systemic serum levels of renin, angiotensin I (Ang I) and angiotensin II (Ang II) were increased and associated with disease progression (p < 0.05) and mortality (p < 0.05). RAAS-activity in pulmonary arteries of iPAH-patients was upregulated, characterized by increased ACE-activity in pulmonary endothelial cells.Findings
Interestingly, Ang II exposure to PA-SMCs of iPAH-patients selectively increased iPAH-PASMC proliferation via enhanced AngII type 1 (AT1) receptor expression and signalling.Findings
In experimental PAH, chronic RAAS-inhibition with an AT1-receptor antagonist (losartan) delayed pulmonary vascular remodelling, decreased right ventricular afterload and restored right ventricular-arterial coupling.Conclusions
Systemic and local RAAS-activity is increased in iPAH-patients and associated with increased pulmonary vascular remodelling. The beneficial effects of an AT1-receptor antagonist warrants further clinical investigation and re-evaluation of the use of RAAS-inhibitors for the treatment of iPAH.