Periostin‐related progression of different types of experimental pulmonary hypertension: A role for <scp>M2</scp> macrophage and <scp>FGF</scp>‐2 signalling
Takashi Yoshida, Tetsutaro Nagaoka, Yuichi Nagata, Yoshifumi Suzuki, Takeo Tsutsumi, Sachiko Kuriyama, Junko Watanabe, Shinsaku Togo, Fumiyuki Takahashi, Masakazu Matsushita, Yusuke Joki, Hakuoh Konishi, Satoshi Nunomura, Kenji Izuhara, Simon J. Conway, Kazuhisa Takahashi
Abstract
Abstract Background and objective Remodelling of pulmonary arteries (PA) contributes to the progression of pulmonary hypertension (PH). Periostin, a matricellular protein, has been reported to be involved in the development of PH. We examined the role of periostin in the pathogenesis of PH using different types of experimental PH. Methods PH was induced by vascular endothelial growth factor receptor antagonist (Sugen5416) plus hypoxic exposure (SuHx) and venous injection of monocrotaline‐pyrrole (MCT‐P) in wild‐type (WT) and periostin −/− mice. Pulmonary haemodynamics, PA remodelling, expression of chemokines and fibroblast growth factor (FGF)‐2, accumulation of macrophages to small PA and the right ventricle (RV) were examined in PH‐induced WT and periostin −/− mice. Additionally, the role of periostin in the migration of macrophages, human PA smooth muscle (HPASMCs) and endothelial cells (HPMVECs) was investigated. Results In PH induced by SuHx and MCT‐P, PH and accumulation of M2 macrophage to small PA were attenuated in periostin −/− mice. PA remodelling post‐SuHx treatment was also mild in periostin −/− mice compared to WT mice. Expression of macrophage‐associated chemokines and FGF‐2 in lung tissue, and accumulation of CD68‐positive cells in the RV were less in SuHx periostin −/− than in SuHx WT mice. Periostin secretion in HPASMCs and HPMVECs was enhanced by transforming growth factor‐β. Periostin also augmented macrophage, HPASMCs and HPMVECs migration. Separately, serum periostin levels were significantly elevated in patients with PH compared to healthy controls. Conclusion Periostin is involved in the development of different types of experimental PH, and may also contribute to the pathogenesis of human PH.