Prevention of pulmonary vascular remodeling and of decreased BMPR-2 expression by losartan therapy in shunt-induced pulmonary hypertension

The renin-ANG system has been reported to be overexpressed in pulmonary arterial hypertension (PAH). We investigated the effects of ANG receptor-1 blockade by losartan on hemodynamics and signaling molecules in a piglet overflow model of early PAH. Twenty-six 3-wk-old piglets were randomized to placebo or losartan therapy (1 mg*[kg.sup.-1]*[day.sup.-1]) after anastomosis of the inominate to the main pulmonary artery or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative-PCR. Chronic systemic-to-pulmonary shunting increased the pulmonary vascular resistance from 2.5 [+ or -] 0.2 to 6.2 [+ or -] 0.3 mmHg*[1.sup.-1]*min*[m.sup.-2] and arteriolar medial thickness from 13.6 to 25.4%. These changes were associated with increased expressions of ANG II and its type 1 (A[T.sub.1]) and type 2 (A[T.sub.2]) receptors, endothelin-1 (ET-1) and its type B receptor (E[T.sub.B]), and angiopoietin-1, together with decreased expressions of bone morphogeneic protein receptor-lA and -2 (BMPR-1A and BMPR-2, respectively) and unchanged expression of the receptor tyrosine kinase with immunoglobulin and EGF homology domains-2 (Tie 2). Pretreatment with losartan decreased shunt-induced pulmonary vascular resistance and medial thickness by 51% and 35%, respectively. Losartan therapy was associated with persistent overexpressions of ANG II, A[T.sub.2], ET-1, E[T.sub.B], and angiopoietin-1 and with a return to normal of the BMPR-2 expression. These results suggest that ANG II contributes to left-to-right, shunt-induced PAH. left-to-right shunt; angiotensin II; endothelin-1; angiopoietin; bone morphogenetic protein receptor-2.