Abstract 15472: Midkine Contributes the Development of Pulmonary Arterial Hypertension via Cell Surface Nucleolin
Background: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease caused by pulmonary arterial remodeling. Midkine is a multifunctional growth factor which regulates cell growth and migration. Hypoxia induces midkine expression in the lung; however the role of midkine on the pathogenesis of pulmonary arterial remodeling remains to be elucidated.
Methods and Results: Chronic hypoxia upregulated midkine expressions in the lung, and induced pulmonary arterial remodeling in wild type (WT) mice. Pulmonary arterial remodeling and right heart hypertrophy were significantly ameliorated in midkine knockout (Mdk-/-) mice comparted with WT mice. In vitro, midkine exposure strongly enhanced the proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) induced by hypoxia. Importantly, hypoxia caused translocation of nucleolin, which functioned as a receptor of midkine, from cytosol to membrane. Silencing of low density lipoprotein receptor-related protein 1 (LRP1) or the use of nucleolin inhibitor, AS1411, attenuated the surface translocation of nucleolin, resulting in the suppression of the midkine-induced phosphorylation of extracellular signal-regulated kinase 1/2, migration and proliferation of PASMCs. To confirm the association between midkine and nucleolin in vivo, Sugen5416-hypoxia induced PAH rats were treated with AS1411. AS1411 significantly decreased right ventricular systolic pressure, pulmonary arterial remodeling, and right heart hypertrophy.
Conclusions: These results indicate that midkine play a crucial role of development of PAH through the surface nucleolin.
Author Disclosures: D. Kinoshita: None. T. Shishido: None. T. Takahashi: None. M. Yokoyama: None. S. Nishiyama: None. H. Takahashi: None. T. Arimoto: None. T. Miyamoto: None. T. Watanabe: None. T. Konta: None. K. Kadomatsu: None. Y. Takeishi: None. I. Kubota: None.
- © 2016 by American Heart Association, Inc.