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MicroRNA-126 overexpression rescues diabetes-induced impairment in efferocytosis of apoptotic cardiomyocytes

Efferocytosis, a process of clearance of apoptotic cells by phagocytes, is essential for successful resolution of inflammation and maintenance of tissue homeostasis. Diabetes compromises the function of macrophages leading to adverse inflammatory response during wound healing, myocardial injury, ath...

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Autores principales: Suresh Babu, Sahana, Thandavarayan, Rajarajan A., Joladarashi, Darukeshwara, Jeyabal, Prince, Krishnamurthy, Shashirekha, Bhimaraj, Arvind, Youker, Keith A., Krishnamurthy, Prasanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101812/
https://www.ncbi.nlm.nih.gov/pubmed/27827458
http://dx.doi.org/10.1038/srep36207
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author Suresh Babu, Sahana
Thandavarayan, Rajarajan A.
Joladarashi, Darukeshwara
Jeyabal, Prince
Krishnamurthy, Shashirekha
Bhimaraj, Arvind
Youker, Keith A.
Krishnamurthy, Prasanna
author_facet Suresh Babu, Sahana
Thandavarayan, Rajarajan A.
Joladarashi, Darukeshwara
Jeyabal, Prince
Krishnamurthy, Shashirekha
Bhimaraj, Arvind
Youker, Keith A.
Krishnamurthy, Prasanna
author_sort Suresh Babu, Sahana
collection PubMed
description Efferocytosis, a process of clearance of apoptotic cells by phagocytes, is essential for successful resolution of inflammation and maintenance of tissue homeostasis. Diabetes compromises the function of macrophages leading to adverse inflammatory response during wound healing, myocardial injury, atherosclerosis and autoimmune disorders. However, the effect of diabetes on macrophage-mediated efferocytosis of apoptotic cardiomyocytes (ACM) and the molecular mechanisms involved are not understood so far. In the present study we found that invitro efferocytosis of ACM was impaired in macrophages from db/db (diabetic) mice. Macrophages exposed to high glucose (HG) decreases microRNA-126 (miR-126) expression with a corresponding increase in ADAM9 expression. Dual-luciferase reporter assay confirms that ADAM9 3′UTR contains miR-126 target site. ADAM9 inhibition reduces HG-induced proteolytic cleavage of Mer tyrosine receptor kinase (MerTK, a proto-oncogene that plays a critical role in phagocytosis), resulting in shedding of soluble-Mer (sMER) and loss of MERTK function. Over-expression of miR-126 attenuates HG-induced impairment of efferocytosis. Furthermore, human diabetic hearts show lower miR-126 expression with a corresponding increase in ADAM9 expression vs. normal counterparts. These data suggests that diabetes impairs efferocytosis of ACM and that strategies to enhance efferocytosis might attenuate diabetes-induced impairment in inflammation resolution and cardiac repair after injury.
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spelling pubmed-51018122016-11-14 MicroRNA-126 overexpression rescues diabetes-induced impairment in efferocytosis of apoptotic cardiomyocytes Suresh Babu, Sahana Thandavarayan, Rajarajan A. Joladarashi, Darukeshwara Jeyabal, Prince Krishnamurthy, Shashirekha Bhimaraj, Arvind Youker, Keith A. Krishnamurthy, Prasanna Sci Rep Article Efferocytosis, a process of clearance of apoptotic cells by phagocytes, is essential for successful resolution of inflammation and maintenance of tissue homeostasis. Diabetes compromises the function of macrophages leading to adverse inflammatory response during wound healing, myocardial injury, atherosclerosis and autoimmune disorders. However, the effect of diabetes on macrophage-mediated efferocytosis of apoptotic cardiomyocytes (ACM) and the molecular mechanisms involved are not understood so far. In the present study we found that invitro efferocytosis of ACM was impaired in macrophages from db/db (diabetic) mice. Macrophages exposed to high glucose (HG) decreases microRNA-126 (miR-126) expression with a corresponding increase in ADAM9 expression. Dual-luciferase reporter assay confirms that ADAM9 3′UTR contains miR-126 target site. ADAM9 inhibition reduces HG-induced proteolytic cleavage of Mer tyrosine receptor kinase (MerTK, a proto-oncogene that plays a critical role in phagocytosis), resulting in shedding of soluble-Mer (sMER) and loss of MERTK function. Over-expression of miR-126 attenuates HG-induced impairment of efferocytosis. Furthermore, human diabetic hearts show lower miR-126 expression with a corresponding increase in ADAM9 expression vs. normal counterparts. These data suggests that diabetes impairs efferocytosis of ACM and that strategies to enhance efferocytosis might attenuate diabetes-induced impairment in inflammation resolution and cardiac repair after injury. Nature Publishing Group 2016-11-09 /pmc/articles/PMC5101812/ /pubmed/27827458 http://dx.doi.org/10.1038/srep36207 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Suresh Babu, Sahana
Thandavarayan, Rajarajan A.
Joladarashi, Darukeshwara
Jeyabal, Prince
Krishnamurthy, Shashirekha
Bhimaraj, Arvind
Youker, Keith A.
Krishnamurthy, Prasanna
MicroRNA-126 overexpression rescues diabetes-induced impairment in efferocytosis of apoptotic cardiomyocytes
title MicroRNA-126 overexpression rescues diabetes-induced impairment in efferocytosis of apoptotic cardiomyocytes
title_full MicroRNA-126 overexpression rescues diabetes-induced impairment in efferocytosis of apoptotic cardiomyocytes
title_fullStr MicroRNA-126 overexpression rescues diabetes-induced impairment in efferocytosis of apoptotic cardiomyocytes
title_full_unstemmed MicroRNA-126 overexpression rescues diabetes-induced impairment in efferocytosis of apoptotic cardiomyocytes
title_short MicroRNA-126 overexpression rescues diabetes-induced impairment in efferocytosis of apoptotic cardiomyocytes
title_sort microrna-126 overexpression rescues diabetes-induced impairment in efferocytosis of apoptotic cardiomyocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101812/
https://www.ncbi.nlm.nih.gov/pubmed/27827458
http://dx.doi.org/10.1038/srep36207
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