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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doaj-ce677c9e462b4e0a836e1d0073a8042d2020-11-24T21:38:51ZengMDPI AGCells2073-44092019-07-018880210.3390/cells8080802cells8080802Hypoxia Promotes Vascular Smooth Muscle Cell Proliferation through microRNA-Mediated Suppression of Cyclin-Dependent Kinase InhibitorsJihui Lee0Hara Kang1Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 406-772, KoreaDivision of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 406-772, KoreaRegulation 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 <i>p15</i>, <i>p16</i>, and <i>p21</i> 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.https://www.mdpi.com/2073-4409/8/8/802vascular smooth muscle cellsmicroRNAscyclin-dependent kinase inhibitorshypoxia |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jihui Lee Hara Kang |
spellingShingle |
Jihui Lee Hara Kang Hypoxia Promotes Vascular Smooth Muscle Cell Proliferation through microRNA-Mediated Suppression of Cyclin-Dependent Kinase Inhibitors Cells vascular smooth muscle cells microRNAs cyclin-dependent kinase inhibitors hypoxia |
author_facet |
Jihui Lee Hara Kang |
author_sort |
Jihui Lee |
title |
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_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_sort |
hypoxia promotes vascular smooth muscle cell proliferation through microrna-mediated suppression of cyclin-dependent kinase inhibitors |
publisher |
MDPI AG |
series |
Cells |
issn |
2073-4409 |
publishDate |
2019-07-01 |
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 <i>p15</i>, <i>p16</i>, and <i>p21</i> 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. |
topic |
vascular smooth muscle cells microRNAs cyclin-dependent kinase inhibitors hypoxia |
url |
https://www.mdpi.com/2073-4409/8/8/802 |
work_keys_str_mv |
AT jihuilee hypoxiapromotesvascularsmoothmusclecellproliferationthroughmicrornamediatedsuppressionofcyclindependentkinaseinhibitors AT harakang hypoxiapromotesvascularsmoothmusclecellproliferationthroughmicrornamediatedsuppressionofcyclindependentkinaseinhibitors |
_version_ |
1725934098941214720 |