Oncotarget

Research Papers: Pathology:

High glucose promotes vascular smooth muscle cell proliferation by upregulating proto-oncogene serine/threonine-protein kinase Pim-1 expression

Keke Wang, Xiaojiang Deng, Zhihua Shen, Yanan Jia, Ranran Ding, Rujia Li, Xiaomin Liao, Sisi Wang, Yanping Ha, Yueqiong Kong, Yuyou Wu, Junli Guo _ and Wei Jie

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Oncotarget. 2017; 8:88320-88331. https://doi.org/10.18632/oncotarget.19368

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Abstract

Keke Wang1,*, Xiaojiang Deng2,*, Zhihua Shen1, Yanan Jia1, Ranran Ding3, Rujia Li1, Xiaomin Liao1, Sisi Wang1, Yanping Ha1, Yueqiong Kong4, Yuyou Wu4, Junli Guo4 and Wei Jie1

1 Department of Pathology, School of Basic medicine Sciences, Guangdong Medical University, Zhanjiang, P.R. China

2 Department of Cardiovascular, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China

3 Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China

4 Cardiovascular Institute of 1st Affiliated Hospital & Key Laboratory of Tropical Diseases and Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, P.R. China

* Joint first authors

Correspondence to:

Junli Guo, email:

Wei Jie, email:

Keywords: high glucose, vascular smooth muscle cell, Pim-1, cell proliferation, STAT3 signaling, Pathology Section

Received: March 09, 2017 Accepted: June 28, 2017 Published: July 18, 2017

Abstract

Serine/threonine kinase proviral integration site for Moloney murine leukemia virus 1 (Pim-1) plays an essential role in arterial wall cell proliferation and associated vascular diseases, including pulmonary arterial hypertension and aortic wall neointima formation. Here we tested a role of Pim-1 in high-glucose (HG)-mediated vascular smooth muscle cell (VSMC) proliferation. Pim-1 and proliferating cell nuclear antigen (PCNA) expression levels in arterial samples from streptozotocin-induced hyperglycemia rats were increased, compared with their weak expression in normoglycemic groups. In cultured rat VSMCs, HG led to transient Pim-1 expression decline, followed by sustained expression increase at both transcriptional and translational levels. Immunoblot analysis demonstrated that HG increased the expression of the 33-kDa isoform of Pim-1, but at much less extent to its 44-kDa plasma membrane isoform. D-glucose at a concentration of 25 mmol/L showed highest activity in stimulating Pim-1 expression. Both Pim-1 inhibitor quercetagetin and STAT3 inhibitor stattic significantly attenuated HG-induced VSMC proliferation and arrested cell cycle progression at the G1 phase. Quercetagetin showed no effect on Pim-1 expression but decreased the phosphorylated-Bad (T112)/Bad ratio in HG-treated VSMCs. However, stattic decreased phosphorylated-STAT3 (Y705) levels and caused transcriptional and translational down-regulation of Pim-1 in HG-treated VSMCs. Our findings suggest HG-mediated Pim-1 expression contributes to VSMC proliferation, which may be partly due to the activation of STAT3/Pim-1 signaling.


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