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

Rondelet, Benoît;Kerbaul, François;Van Beneden, Ronald;Hubloue, Ives;Naeije, Robert;et.al.
(2005) American Journal of Physiology: Heart and Circulatory Physiology — Vol. 289, n° 6 58-6, p. H2319-H2324 (2005)

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  • Rondelet, BenoîtUCLouvain
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  • Kerbaul, FrançoisULB
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  • Van Beneden, RonaldULB
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  • Hubloue, IvesULB
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  • Naeije, RobertULB
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Abstract
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 randonmed 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·1 -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 (ETB), 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, ETB, 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. Copyright © 2005 the American Physiological Society.
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Rondelet, B., Kerbaul, F., Van Beneden, R., Hubloue, I., Huez, S., Fesler, P., Remmelink, M., Brimioulle, S., Salmon, I., & Naeije, R. (2005). Prevention of pulmonary vascular remodeling and of decreased BMPR-2 expression by losartan therapy in shunt-induced pulmonary hypertension. American Journal of Physiology: Heart and Circulatory Physiology, 289(6 58-6), H2319-H2324. https://doi.org/10.1152/ajpheart.00518.2005 (Original work published 2005)