Elevated expression levels of miR-143/5 in saphenous vein smooth muscle cells from patients with Type 2 diabetes drive persistent changes in phenotype and function

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Abstract

Type 2 diabetes (T2DM) promotes premature atherosclerosis and inferior prognosis after arterial reconstruction. Vascular smooth muscle cells (SMC) respond to patho/physiological stimuli, switching between quiescent contractile and activated synthetic phenotypes under the control of microRNAs (miRs) that regulate multiple genes critical to SMC plasticity. The importance of miRs to SMC function specifically in T2DM is unknown. This study was performed to evaluate phenotype and function in SMC cultured from non-diabetic and T2DM patients, to explore any aberrancies and investigate underlying mechanisms. Saphenous vein SMC cultured from T2DM patients (T2DM-SMC) exhibited increased spread cell area, disorganised cytoskeleton and impaired proliferation relative to cells from non-diabetic patients (ND-SMC), accompanied by a persistent, selective up-regulation of miR-143 and miR-145. Transfection of premiR-143/145 into ND-SMC induced morphological and functional characteristics similar to native T2DM-SMC; modulating miR-143/145 targets Kruppel-like factor 4, alpha smooth muscle actin and myosin VI. Conversely, transfection of antimiR-143/145 into T2DM-SMC conferred characteristics of the ND phenotype. Exposure of ND-SMC to transforming growth factor beta (TGFβ) induced a diabetes-like phenotype; elevated miR-143/145, increased cell area and reduced proliferation. Furthermore, these effects were dependent on miR-143/145. In conclusion, aberrant expression of miR-143/145 induces a distinct saphenous vein SMC phenotype that may contribute to vascular complications in patients with T2DM, and is potentially amenable to therapeutic manipulation.

Highlights

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Patients with T2DM are vulnerable to premature cardiovascular vascular disease
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SV-SMC from T2DM donors exhibit a distinct phenotype and functional aberrancies
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miR-143 + 145 are up-regulated in T2DM-SMC and modulate morphology and proliferation
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Plasma TGFβ is elevated in T2DM and can stimulate miR-143 + 145 expression in SMC
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TGFβ-induced miR-143 + 145 may induce SMC dysfunction and represent novel targets

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Most cited references 49

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miR-145 and miR-143 Regulate Smooth Muscle Cell Fate Decisions

Kimberly Cordes, Neil T. Sheehy, Mark White … (2009)

SUMMARY microRNAs are regulators of myriad cellular events, but evidence for a single microRNA that can efficiently differentiate multipotent cells into a specific lineage or regulate direct reprogramming of cells into an alternate cell fate has been elusive. Here, we show that miR-145 and miR-143 are co-transcribed in multipotent cardiac progenitors before becoming localized to smooth muscle cells, including neural crest stem cell–derived vascular smooth muscle cells. miR-145 and miR-143 were direct transcriptional targets of serum response factor, myocardin and Nkx2.5, and were downregulated in injured or atherosclerotic vessels containing proliferating, less differentiated smooth muscle cells. miR-145 was necessary for myocardin-induced reprogramming of adult fibroblasts into smooth muscle cells and sufficient to induce differentiation of multipotent neural crest stem cells into vascular smooth muscle. Furthermore, miR-145 and miR-143 cooperatively targeted a network of transcription factors, including Klf4, myocardin, and Elk-1 to promote differentiation and repress proliferation of smooth muscle cells. These findings demonstrate that miR-145 can direct the smooth muscle fate and that miR-145 and miR-143 function to regulate the quiescent versus proliferative phenotype of smooth muscle cells.

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Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia

Assam El-Osta, Daniella Brasacchio, Dachun Yao … (2008)

The current goal of diabetes therapy is to reduce time-averaged mean levels of glycemia, measured as HbA1c, to prevent diabetic complications. However, HbA1c only explains <25% of the variation in risk of developing complications. Because HbA1c does not correlate with glycemic variability when adjusted for mean blood glucose, we hypothesized that transient spikes of hyperglycemia may be an HbA1c–independent risk factor for diabetic complications. We show that transient hyperglycemia induces long-lasting activating epigenetic changes in the promoter of the nuclear factor κB (NF-κB) subunit p65 in aortic endothelial cells both in vitro and in nondiabetic mice, which cause increased p65 gene expression. Both the epigenetic changes and the gene expression changes persist for at least 6 d of subsequent normal glycemia, as do NF-κB–induced increases in monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1 expression. Hyperglycemia-induced epigenetic changes and increased p65 expression are prevented by reducing mitochondrial superoxide production or superoxide-induced α-oxoaldehydes. These results highlight the dramatic and long-lasting effects that short-term hyperglycemic spikes can have on vascular cells and suggest that transient spikes of hyperglycemia may be an HbA1c–independent risk factor for diabetic complications.

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Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism.

Sabine Jordan, Markus Krüger, Diana M Willmes … (2011)

The contribution of altered post-transcriptional gene silencing to the development of insulin resistance and type 2 diabetes mellitus so far remains elusive. Here, we demonstrate that expression of microRNA (miR)-143 and 145 is upregulated in the liver of genetic and dietary mouse models of obesity. Induced transgenic overexpression of miR-143, but not miR-145, impairs insulin-stimulated AKT activation and glucose homeostasis. Conversely, mice deficient for the miR-143-145 cluster are protected from the development of obesity-associated insulin resistance. Quantitative-mass-spectrometry-based analysis of hepatic protein expression in miR-143-overexpressing mice revealed miR-143-dependent downregulation of oxysterol-binding-protein-related protein (ORP) 8. Reduced ORP8 expression in cultured liver cells impairs the ability of insulin to induce AKT activation, revealing an ORP8-dependent mechanism of AKT regulation. Our experiments provide direct evidence that dysregulated post-transcriptional gene silencing contributes to the development of obesity-induced insulin resistance, and characterize the miR-143-ORP8 pathway as a potential target for the treatment of obesity-associated diabetes. © 2011 Macmillan Publishers Limited. All rights reserved

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Author and article information

Contributors

Karen E. Porter

Journal

Journal ID (nlm-ta): J Mol Cell Cardiol

Journal ID (iso-abbrev): J. Mol. Cell. Cardiol

Title: Journal of Molecular and Cellular Cardiology

Publisher: Academic Press

ISSN (Print): 0022-2828

ISSN (Electronic): 1095-8584

Publication date PMC-release: 1 September 2014

Publication date (Print): September 2014

Volume: 74

Issue: 100

Pages: 240-250

Affiliations

[a ]Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, UK

[b ]Multidisciplinary Cardiovascular Research Centre (MCRC), University of Leeds, Leeds, UK

[c ]Department of Cardiac Surgery, The Yorkshire Heart Centre, Leeds General Infirmary, Leeds, UK

[d ]School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, UK

Author notes

[* ]Corresponding author at: Division of Cardiovascular and Diabetes Research, Worsley Building, Clarendon Way, University of Leeds, Leeds LS2 9JT, UK. Tel.: + 44 113 3434806; fax: + 44 113 3434803. medkep@ 123456leeds.ac.uk

Article

Publisher ID: S0022-2828(14)00194-1

DOI: 10.1016/j.yjmcc.2014.05.018

PMC ID: 4121534

PubMed ID: 24927876

SO-VID: 7a37e5af-e250-4bd7-83f4-46a56fb27d93

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

History

Date received : 3 January 2014

Date revision received : 28 May 2014

Date accepted : 31 May 2014

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Elevated expression levels of miR-143/5 in saphenous vein smooth muscle cells from patients with Type 2 diabetes drive persistent changes in phenotype and function

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Stress signalling in stem cells

Most cited references 49

miR-145 and miR-143 Regulate Smooth Muscle Cell Fate Decisions

Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia

Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism.

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