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Hypoxia Promotes Vascular Smooth Muscle Cell Proliferation through microRNA-Mediated Suppression of Cyclin-Dependent Kinase Inhibitors

Regulation of vascular smooth muscle cell (VSMC) proliferation is essential to maintain vascular homeostasis. Hypoxia induces abnormal proliferation of VSMCs and causes vascular proliferative disorders, such as pulmonary hypertension and atherosclerosis. As several cyclin/cyclin-dependent kinase (CD...

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Detalles Bibliográficos
Autores principales: Lee, Jihui, Kang, Hara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721514/
https://www.ncbi.nlm.nih.gov/pubmed/31370272
http://dx.doi.org/10.3390/cells8080802
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author Lee, Jihui
Kang, Hara
author_facet Lee, Jihui
Kang, Hara
author_sort Lee, Jihui
collection PubMed
description Regulation of vascular smooth muscle cell (VSMC) proliferation is essential to maintain vascular homeostasis. Hypoxia induces abnormal proliferation of VSMCs and causes vascular proliferative disorders, such as pulmonary hypertension and atherosclerosis. As several cyclin/cyclin-dependent kinase (CDK) complexes and CDK inhibitors (CKIs) control cell proliferation, in this study, we investigated CKIs involved in the hypoxia-induced proliferation process of human primary pulmonary artery smooth muscle cells to understand the underlying molecular mechanism. We demonstrated that p15, p16, and p21 are downregulated in pulmonary artery smooth muscle cells when exposed to hypoxia. In addition, we identified novel hypoxia-induced microRNAs (hypoxamiRs) including miR-497, miR-1268a, and miR-665 that are upregulated under hypoxia and post-transcriptionally regulate p15, p16, and p21 genes, respectively, by directly targeting their 3’UTRs. These miRNAs promoted the proliferation of VSMCs, and their inhibition decreased VSMC proliferation even in hypoxic conditions. Overall, this study revealed that miRNA-mediated regulatory mechanism of CKIs is essential for hypoxia-induced proliferation of VSMCs. These findings provide insights for a better understanding of the pathogenesis of vascular proliferative disorders.
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spelling pubmed-67215142019-09-10 Hypoxia Promotes Vascular Smooth Muscle Cell Proliferation through microRNA-Mediated Suppression of Cyclin-Dependent Kinase Inhibitors Lee, Jihui Kang, Hara Cells Article Regulation of vascular smooth muscle cell (VSMC) proliferation is essential to maintain vascular homeostasis. Hypoxia induces abnormal proliferation of VSMCs and causes vascular proliferative disorders, such as pulmonary hypertension and atherosclerosis. As several cyclin/cyclin-dependent kinase (CDK) complexes and CDK inhibitors (CKIs) control cell proliferation, in this study, we investigated CKIs involved in the hypoxia-induced proliferation process of human primary pulmonary artery smooth muscle cells to understand the underlying molecular mechanism. We demonstrated that p15, p16, and p21 are downregulated in pulmonary artery smooth muscle cells when exposed to hypoxia. In addition, we identified novel hypoxia-induced microRNAs (hypoxamiRs) including miR-497, miR-1268a, and miR-665 that are upregulated under hypoxia and post-transcriptionally regulate p15, p16, and p21 genes, respectively, by directly targeting their 3’UTRs. These miRNAs promoted the proliferation of VSMCs, and their inhibition decreased VSMC proliferation even in hypoxic conditions. Overall, this study revealed that miRNA-mediated regulatory mechanism of CKIs is essential for hypoxia-induced proliferation of VSMCs. These findings provide insights for a better understanding of the pathogenesis of vascular proliferative disorders. MDPI 2019-07-31 /pmc/articles/PMC6721514/ /pubmed/31370272 http://dx.doi.org/10.3390/cells8080802 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Jihui
Kang, Hara
Hypoxia Promotes Vascular Smooth Muscle Cell Proliferation through microRNA-Mediated Suppression of Cyclin-Dependent Kinase Inhibitors
title Hypoxia Promotes Vascular Smooth Muscle Cell Proliferation through microRNA-Mediated Suppression of Cyclin-Dependent Kinase Inhibitors
title_full Hypoxia Promotes Vascular Smooth Muscle Cell Proliferation through microRNA-Mediated Suppression of Cyclin-Dependent Kinase Inhibitors
title_fullStr Hypoxia Promotes Vascular Smooth Muscle Cell Proliferation through microRNA-Mediated Suppression of Cyclin-Dependent Kinase Inhibitors
title_full_unstemmed Hypoxia Promotes Vascular Smooth Muscle Cell Proliferation through microRNA-Mediated Suppression of Cyclin-Dependent Kinase Inhibitors
title_short Hypoxia Promotes Vascular Smooth Muscle Cell Proliferation through microRNA-Mediated Suppression of Cyclin-Dependent Kinase Inhibitors
title_sort hypoxia promotes vascular smooth muscle cell proliferation through microrna-mediated suppression of cyclin-dependent kinase inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721514/
https://www.ncbi.nlm.nih.gov/pubmed/31370272
http://dx.doi.org/10.3390/cells8080802
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