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, 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.
Department of Cardiovascular Sciences, Centre for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA.
Sahana
S
Suresh Babu
Department of Cardiovascular Sciences, Centre for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA.
Rajarajan A
RA
Thandavarayan
Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, AL 35294, USA.
Darukeshwara
D
Joladarashi
Department of Cardiovascular Sciences, Centre for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA.
Prince
P
Jeyabal
Department of Cardiovascular Sciences, Centre for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA.
Shashirekha
S
Krishnamurthy
Houston Methodist DeBakey Heart &Vascular Center, Houston Methodist Hospital, Houston, Texas, USA.
Arvind
A
Bhimaraj
Houston Methodist DeBakey Heart &Vascular Center, Houston Methodist Hospital, Houston, Texas, USA.
Keith A
KA
Youker
Department of Cardiovascular Sciences, Centre for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA.|Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, AL 35294, USA.
Prasanna
P
Krishnamurthy
D020413:3' Untranslated Regions; D051722:ADAM Proteins / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000166:cytology*; D010587:Phagocytosis; D000090063:Proto-Oncogene Mas; D000067996:RAW 264.7 Cells; D000074084:THP-1 Cells; D000076202:c-Mer Tyrosine Kinase / Q000378:metabolism
D020413:3' Untranslated Regions; C000715470:MAS1 protein, human; C527111:MIRN126 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; C097072:MERTK protein, human; D000076202:c-Mer Tyrosine Kinase; D051722:ADAM Proteins; C098339:ADAM9 protein, human; D005947:Glucose