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

Abstract

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.

The Role of Leukocytes in Diabetic Cardiomyopathy

“…Normally in injured tissue, macrophages engulf apoptotic cells and cellular debris to reduce inflammation, a phenomenon called efferocytosis ( DeBerge et al, 2017 ). Several molecular processes contribute to this mechanism and in particular the metalloproteinase disintegrin and metalloproteinase domain-containing protein 9 (ADAM-9) was shown to be upregulated in macrophages under conditions of high glucose, secondary to decreased expression of miR-126, which increased MER proto-oncogene, tyrosine kinase (MerTK) cleavage to ultimately reduce efferocytosis ( Suresh Babu et al, 2016 ). Importantly, human diabetic hearts displayed the same molecular signatures in terms of miR-126, ADAM9, and cleaved MerTK expression, suggesting this process may be involved in regulating human DCM progression.…”

Increased Expression of Resistin in MicroRNA-155-Deficient White Adipose Tissues May Be a Possible Driver of Metabolically Healthy Obesity Transition to Classical Obesity

“…More specifically, miRNAs in these four HRDs have been identified as protective against oxidative stress or as promoting oxidative stress. For instance, miR-210 ( Ying et al, 2017 ) in atherosclerosis, miR-378 ( Carrer et al, 2012 ) in obesity, miR-34a ( Derdak et al, 2013 ) in NAFLD, miR-126 ( Suresh Babu et al, 2016 ) in T2DM. These experimental findings demonstrate that miRNAs help to mediate protective effects against or damaging effects of oxidation species.…”

MicroRNA as a Therapeutic Target in Cardiac Remodeling

“…miR-126 promotes the efferocytosis in myocardial tissue. However, the reduction of its expression under diabetic condition impairs the clearance of dead cardiomyocytes, which consequently leads to prolonged inflammation process [153]. Similarly, miR-145-5p can inhibit the CD40 mediated inflammatory response and cardiomyocyte cell death caused by acute hypoxia.…”