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This Article Full Text Full Text (PDF) All Versions of this Article: 289/6/H2319    most recent 00518.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Rondelet, B. Articles by Naeije, R. Search for Related Content PubMed PubMed Citation Articles by Rondelet, B. Articles by Naeije, R.

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

¹Laboratory of Physiology, Faculty of Medicine, and ²Department of Pathology, Erasme Hospital, Free University of Brussels, Brussels, Belgium; and ³Department of Anesthesiology and Critical Care, La Timone Hospital, Marseille, France

Submitted 18 May 2005 ; accepted in final form 11 July 2005

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^–1·day^–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 ± 0.2 to 6.2 ± 0.3 mmHg·l^–1·min·m^–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 (AT₁) and type 2 (AT₂) receptors, endothelin-1 (ET-1) and its type B receptor (ET_B), and angiopoietin-1, together with decreased expressions of bone morphogeneic protein receptor-1A 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, AT₂, ET-1, ET_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.

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