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. 2020 Jun 25;10:10345. doi: 10.1038/s41598-020-67217-w

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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AS1411 suppresses the development of pulmonary arterial hypertension (PAH) by inhibiting midkine (MK)-nucleolin (NCL)-EGFR axis. (a) Pulmonary arterial smooth muscle cells (PASMCs) were treated with vehicle or AS1411, which was followed with the treatment with biotinylated MK. Full-length blots are presented in Supplementary Figure 11. (b) Phosphorylated ERK1/2 and EGFR (p-ERK1/2 and p-EGFR) and total ERK1/2 and EGFR (t-ERK1/2 and t-EGFR) expression levels in PASMCs treated with MK after AS1411 pretreatment. Full-length blots are presented in Supplementary Figure 12. (c) Representative images of MK-induced migration of PASMCs after the pretreatment of cells with placebo and AS1411, and its quantification using ImageJ software (version 1.42; https://imagej.nih.gov/ij/). (d) MK-induced proliferation of PASMCs under hypoxic conditions. (e) Study design. Rats were divided into three groups, and the rats were treated with AS1411 (10 mg/kg/day) or the vehicle for consecutive 5 days after the establishment of PAH. Normoxic control was treated with vehicle and exposed to hypoxic conditions for 3 weeks, which was followed by the re-exposure to normoxia. (f) Western blot analysis midkine (MK) and β-tubulin expression in lung homogenates, and their quantification. Full-length blots are presented in Supplementary Figure 13. (g) Right ventricular systolic pressure (RVSP) was assessed following the treatment with AS1411 (n = 4). (h) The ratio of pulmonary artery acceleration time (PAAT) and pulmonary artery ejection time (PAET), assessed by echocardiography (n = 4). (i) Analysis of RV chamber area was assessed at the papillary muscle level using B-mode (n = 4). (j) RV hypertrophy assessed by RV/left ventricle plus septum (LV + S). (k) Representative images of Elastica-Masson staining demonstrating the occlusive pulmonary arterial remodeling in Sugen/hypoxia (SuHx) rats. Scale bar, 20 µm; (n = 5). (l) PCNA (red), α-smooth muscle actin (SMA, green), and DAPI (Blue) lung section immunostaining in SuHx. PCNA-positive smooth muscle cells were counted in at least 20 distal pulmonary arteries (external diameter <50 µm); (n = 5). *ANOVA post-hoc Tukey’s honest significant difference, P < 0.05, compared with the indicated control.