Periostin-expressing cell-specific transforming growth factor-β inhibition in pulmonary artery prevents pulmonary arterial hypertension

• Published in: PloS one 2019-08, Vol.14 (8), p.e0220795-e0220795
• Main Authors: Seki, Mitsuru, Furukawa, Nozomi, Koitabashi, Norimichi, Obokata, Masaru, Conway, Simon J, Arakawa, Hirokazu, Kurabayashi, Masahiko
• Format: Article
• Language: English
• Subjects: Animals; Biology and life sciences; Cell activation; Cell adhesion & migration; Cell Adhesion Molecules - metabolism; Cell Adhesion Molecules - pharmacology; Experiments; Extracellular matrix; Fibroblasts; Fluorescence; Growth factors; Heart; Hemodynamics; Hypertension; Hypertension, Pulmonary - metabolism; Hypoxia; Hypoxia - metabolism; Inhibition; Kinases; Lung - pathology; Lungs; Male; Medicine; Medicine and Health Sciences; Mice; Mice, Knockout; Muscle, Smooth, Vascular - metabolism; Oxygen; Pathogenesis; Pediatrics; Proteins; Pulmonary Arterial Hypertension - metabolism; Pulmonary Arterial Hypertension - physiopathology; Pulmonary arteries; Pulmonary artery; Pulmonary Artery - pathology; Pulmonary fibrosis; Pulmonary hypertension; Receptors, Transforming Growth Factor beta - metabolism; Research and Analysis Methods; Rodents; Signal Transduction; Signaling; Smad3 protein; Smooth muscle; Thickening; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - physiology; Transforming growth factor-b; Transforming Growth Factors - metabolism; Transgenic animals; University graduates; Veins & arteries; Ventricle
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0220795

Transforming growth factor beta (TGF-β) has been shown to play a critical role in pathogenesis of pulmonary arterial hypertension (PAH) although the precise role of TGF-β signaling remains uncertain. A recent report has shown that periostin (Pn) is one of the most upregulated proteins in human PAH lung compared with healthy lungs. We established type I TGF-β receptor knockout mice specifically with Pn expressing cell (Pn-Cre/Tgfb1fl/fl mice). Increases in PA pressure and pulmonary artery muscularization were induced by hypoxia of 10% oxygen for 4 weeks. Lung Pn expression was markedly induced by 4 week-hypoxia. Pn-Cre/Tgfb1fl/fl mice showed lower right ventricular pressure elevation, inhibition of PA medial thickening. Fluorescent co-immunostaining showed that Smad3 activation in Pn expressing cell is attenuated. These results suggest that TGF-β signaling in Pn expressing cell may have an important role in the pathogenesis of PAH by controlling medial thickening.