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Pioglitazone protects blood vessels through inhibition of the apelin signaling pathway by promoting KLF4 expression in rat models of T2DM
Apelin, identified as the endogenous ligand of APJ, exerts various cardiovascular effects. However, the molecular mechanism underlying the regulation of apelin expression in vascular cells is poorly described. Pioglitazone (PIO) and Krüppel-like factor 4 (KLF4) exhibit specific biological functions...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928522/ https://www.ncbi.nlm.nih.gov/pubmed/31829402 http://dx.doi.org/10.1042/BSR20190317 |
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author | Wang, Ying Zhang, Ruonan Shen, Hailin Kong, Jing Lv, Xinrui |
author_facet | Wang, Ying Zhang, Ruonan Shen, Hailin Kong, Jing Lv, Xinrui |
author_sort | Wang, Ying |
collection | PubMed |
description | Apelin, identified as the endogenous ligand of APJ, exerts various cardiovascular effects. However, the molecular mechanism underlying the regulation of apelin expression in vascular cells is poorly described. Pioglitazone (PIO) and Krüppel-like factor 4 (KLF4) exhibit specific biological functions on vascular physiology and pathophysiology by regulating differentiation- and proliferation-related genes. The present study aimed to investigate the roles of PIO and KLF4 in the transcriptional regulation of apelin in a high-fat diet/streptozotocin rat model of diabetes and in PIO-stimulated vascular smooth muscle cells (VSMCs). Immunohistochemistry, qRT-PCR, and Western blotting assays revealed that the aorta of the Type 2 diabetes mellitus (T2DM) rat models had a high expression of apelin, PIO could decrease the expression of apelin in the PIO-treated rats. In vitro, Western blotting assays and immunofluorescent staining results showed that the basal expression of apelin was decreased but that of KLF4 was increased when VSMCs were stimulated by PIO treatment. Luciferase and chromatin immunoprecipitation assay results suggested that KLF4 bound to the GKLF-binding site of the apelin promoter and negatively regulated the transcription activity of apelin in VSMCs under PIO stimulation. Furthermore, qRT-PCR and Western blotting assay results showed that the overexpression of KLF4 markedly decreased the basal expression of apelin, but the knockdown of KLF4 restored the PIO-induced expression of apelin. In conclusion, PIO inhibited the expression of apelin in T2DM rat models to prevent diabetic macroangiopathy, and negatively regulated the gene transcription of apelin by promoting transcription of KLF4 in the apelin promoter. |
format | Online Article Text |
id | pubmed-6928522 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-69285222020-01-02 Pioglitazone protects blood vessels through inhibition of the apelin signaling pathway by promoting KLF4 expression in rat models of T2DM Wang, Ying Zhang, Ruonan Shen, Hailin Kong, Jing Lv, Xinrui Biosci Rep Cardiovascular System & Vascular Biology Apelin, identified as the endogenous ligand of APJ, exerts various cardiovascular effects. However, the molecular mechanism underlying the regulation of apelin expression in vascular cells is poorly described. Pioglitazone (PIO) and Krüppel-like factor 4 (KLF4) exhibit specific biological functions on vascular physiology and pathophysiology by regulating differentiation- and proliferation-related genes. The present study aimed to investigate the roles of PIO and KLF4 in the transcriptional regulation of apelin in a high-fat diet/streptozotocin rat model of diabetes and in PIO-stimulated vascular smooth muscle cells (VSMCs). Immunohistochemistry, qRT-PCR, and Western blotting assays revealed that the aorta of the Type 2 diabetes mellitus (T2DM) rat models had a high expression of apelin, PIO could decrease the expression of apelin in the PIO-treated rats. In vitro, Western blotting assays and immunofluorescent staining results showed that the basal expression of apelin was decreased but that of KLF4 was increased when VSMCs were stimulated by PIO treatment. Luciferase and chromatin immunoprecipitation assay results suggested that KLF4 bound to the GKLF-binding site of the apelin promoter and negatively regulated the transcription activity of apelin in VSMCs under PIO stimulation. Furthermore, qRT-PCR and Western blotting assay results showed that the overexpression of KLF4 markedly decreased the basal expression of apelin, but the knockdown of KLF4 restored the PIO-induced expression of apelin. In conclusion, PIO inhibited the expression of apelin in T2DM rat models to prevent diabetic macroangiopathy, and negatively regulated the gene transcription of apelin by promoting transcription of KLF4 in the apelin promoter. Portland Press Ltd. 2019-12-24 /pmc/articles/PMC6928522/ /pubmed/31829402 http://dx.doi.org/10.1042/BSR20190317 Text en © 2019 The Author(s). https://creativecommons.org/licenses/by/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). |
spellingShingle | Cardiovascular System & Vascular Biology Wang, Ying Zhang, Ruonan Shen, Hailin Kong, Jing Lv, Xinrui Pioglitazone protects blood vessels through inhibition of the apelin signaling pathway by promoting KLF4 expression in rat models of T2DM |
title | Pioglitazone protects blood vessels through inhibition of the apelin signaling pathway by promoting KLF4 expression in rat models of T2DM |
title_full | Pioglitazone protects blood vessels through inhibition of the apelin signaling pathway by promoting KLF4 expression in rat models of T2DM |
title_fullStr | Pioglitazone protects blood vessels through inhibition of the apelin signaling pathway by promoting KLF4 expression in rat models of T2DM |
title_full_unstemmed | Pioglitazone protects blood vessels through inhibition of the apelin signaling pathway by promoting KLF4 expression in rat models of T2DM |
title_short | Pioglitazone protects blood vessels through inhibition of the apelin signaling pathway by promoting KLF4 expression in rat models of T2DM |
title_sort | pioglitazone protects blood vessels through inhibition of the apelin signaling pathway by promoting klf4 expression in rat models of t2dm |
topic | Cardiovascular System & Vascular Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928522/ https://www.ncbi.nlm.nih.gov/pubmed/31829402 http://dx.doi.org/10.1042/BSR20190317 |
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