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(-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 (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.
Rondelet
Benoît
B
Laboratory of Physiology, Free Univ. of Brussels, Erasmus Campus CP 604, Lennik Rd. 808, B-1070 Brussels, Belgium. benoit.rondelet@ulb.ac.be
Kerbaul
François
F
Van Beneden
Ronald
R
Hubloue
Ives
I
Huez
Sandrine
S
Fesler
Pierre
P
Remmelink
Myriam
M
Brimioulle
Serge
S
Salmon
Isabelle
I
Naeije
Robert
R
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism*; D019808:Losartan / Q000008:administration & dosage*; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013552:Swine; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D019808:Losartan