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Introduction Pulmonary arterial hypertension (PAH) is characterized by the progressive pulmonary vascular obstruction, although the precise cause remains unclear. The pathologic thickening of the arterial wall is considered to include [...], The increase in thickening of the arterial wall of pulmonary arterial hypertension (PAH) includes cellular proliferation as well as matrix deposition and interrupted internal elastic lamina (IEL) consisting of a thick homogeneous sheet of elastin. Little is, although, known about the detail of IEL formation in PAH. Endothelin-1 is overexpressed in pulmonary arterioles of PAH. We aimed to examine the expression of genes contributing to IEL formation in pulmonary artery smooth muscle cells (PASMCs) especially focused on lysyl oxidase (LOx), an exreacellular matrix enzyme that catalyzes the cross-linking of collagens or elastin. We quantified mRNA expressions of genes contributing to IEL formation including LOx in PASMCs using real-time quantitative polymerase chain reaction. We stimulated human PASMCs with endothelin-1 with prostacyclin or trapidil. Endothelin-1 significantly increased LOx expression. Prostacyclin and trapidil restored endothelin-1-induced LOx expression to the basal level. Endothelin-1 increased LOx expression strongly in PASMCs from PAH patients compared to those from controls. Trapidil reduced LOx expression only in PASMCs from PAH patients. Overexpressed endothelin-1 in PAH patients can increase expression of LOx and agitate cross-linking of elastin and collagen, resulting in ectopic deposition of these in the vascular media. Key words: elastin, lysyl oxidase, endothelin, pulmonary artery smooth muscle cells, pulmonary hypertension. L'augmentation de l'epaississement de la paroi arterielle dans l'hypertension arterielle pulmonaire (HAP) comprend la proliferation des cellules, ainsi que le depot de matrice avec des interruptions dans la limitante elastique interne (LEI) constituee d'une couche d'elastine epaisse et homogene. Mais on sait peu de choses des details de la formation de la LEI dans l'HAP. En cas d'HAP, l'endotheline 1 est surexprimee dans les arterioles pulmonaires. Nous visions a examiner l'expression de genes contribuant a la formation de la LEI dans les cellules musculaires lisses d'artere pulmonaire (CMLAP), en nous centrant particulierement sur la lysyl oxydase (LOx), une enzyme de la matrice extracellulaire qui catalyse la reticulation du collagene ou de l'elastine. A l'aide de la technique de PCR quantitatif en temps reel, nous avons quantifie l'expression de l'ARNm de genes participant a la formation de la LEI, y compris l'enzyme LOx, dans les CMLAP. Nous avons stimule des CMLAP humains avec de l'endotheline 1, et avec de la prostacycline ou du trapidil. L'endotheline entrainait une augmentation marquee de l'expression de la LOx. Avec la prostacycline et le trapidil, l'expression de la LOx engendree par l'endotheline se retablissait aux valeurs du debut de l'experience. L'endotheline 1 a entraine une plus forte augmentation de l'expression de la LOx dans les CMLAP des patients atteints d'HAP que chez les temoins. Le trapidil a entraine une diminution de l'expression de la LOx uniquement dans les CMLAP des patients atteints d'HAP. En conclusion, la surexpression de l'endotheline 1 chez les patients atteints d'HAP peut entrainer une augmentation de l'expression de la LOx et troubler la reticulation de l'elastine et du collagene, ce qui se traduit par leur depot ectopique dans la media vasculaire. Mots-cles: elastine, lysyl oxydase, endotheline, cellules musculaires lisses d'artere pulmonaire, hypertension pulmonaire.

Experimental left-to-right shunt-induced pulmonary arterial hypertension (PAH) can be partially prevented by the endothelin-A receptor blocker sitaxsentan or by the phosphodiesterase-5 inhibitor sildenafil. We hypothesized that the combined administration of these drugs would completely prevent shunt-induced PAH, arguing in favor of a major role of endothelial dysfunction in the initiation of the disease. Twenty-four 3-wk-old piglets were randomized to a sham operation or to placebo, sitaxsentan therapy, or sitaxsentan combined with sildenafil after the anastomosis of the left subclavian artery to the pulmonary arterial trunk. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry and quantitative real-time PCR for endothelin-1, angiopoietin-1, and bone morphogenetic protein receptor (BMPR) signaling molecules. Three months of left-to-right shunting induced an increase in pulmonary vascular resistance (PVR) and medial thickness, an overexpression of endothelin-1, and angiopoietin-1 and decreased expressions of BMPR-2 and BMPR-1A. Sitaxsentan partially prevented a shunt-induced increase in PVR, medial thickness, and associated biological disturbances. Sildenafil combined with sitaxsentan normalized PVR, medial thickness, and the expression of endothelin-1. However, the expression of angiopoietin-1 remained increased, and the expressions of BMPR-1A and BMPR-2 were incompletely returned to normal. The coupling of fight ventricular end-systolic to arterial elastances was maintained in all circumstances. Sitaxsentan combined with sildenafil prevents shunt-induced PAH more effectively than sitaxsentan alone, suggesting a major role for the targeted signaling pathways in the initiation of the disease. Sitaxsentan alone or combined with sildenafil did not affect fight ventricular function. combination therapy; left-to-fight shunt; congenital heart disease; fight ventricle doi: 10.1152/ajpheart.00418.2010.