Hyperglycemic Myocardial Damage Is Mediated by Proinflammatory Cytokine: Macrophage Migration Inhibitory Factor

Abstract

BackgroundDiabetes has been regarded as an inflammatory condition which is associated with left ventricular diastolic dysfunction (LVDD). The purpose of this study was to examine the expression levels of macrophage migration inhibitory factor (MIF) and G protein-coupled receptor kinase 2 (GRK2) in patients with early diabetic cardiomyopathy, and to investigate the mechanisms involved in MIF expression and GRK2 activation.Methods83 patients in the age range of 30-64 years with type 2 diabetes and 30 matched healthy men were recruited. Left ventricular diastolic function was evaluated by cardiac Doppler echocardiography. Plasma MIF levels were determined by ELISA. To confirm the clinical observation, we also studied MIF expression in prediabetic rats with impaired glucose tolerance (IGT) and relationship between MIF and GRK2 expression in H9C2 cardiomyoblasts exposed to high glucose.ResultsCompared with healthy subjects, patients with diabetes have significantly increased levels of plasma MIF which was further increased in diabetic patients with Left ventricular diastolic dysfunction (LVDD). The increased plasma MIF levels in diabetic patients correlated with plasma glucose, glycosylated hemoglobin and urine albumin levels. We observed a significant number of TUNEL-positive cells in the myocardium of IGT-rats but not in the control rats. Moreover, we found higher MIF expression in the heart of IGT with cardiac dysfunction compared to that of the controls. In H9C2 cardiomyoblast cells, MIF and GRK2 expression was significantly increased in a glucose concentration-dependant manner. Furthermore, GRK2 expression was abolished by siRNA knockdown of MIF and by the inhibition of CXCR4 in H9C2 cells.ConclusionsOur findings indicate that hyperglycemia is a causal factor for increased levels of pro-inflammatory cytokine MIF which plays a role in the development of cardiomyopathy occurring in patients with type 2 diabetes. The elevated levels of MIF are associated with cardiac dysfunction in diabetic patients, and the MIF effects are mediated by GRK2.

Macrophage Migration Inhibitory Factor Inhibition Is Deleterious for High-Fat Diet-Induced Cardiac Dysfunction

“…Interestingly, we detected that heart increased its endogenous production of MIF. While this autocrine/endocrine function has been previously illustrated in sepsis [14] and ischemia/reperfusion injury [18], the overall cardiac effects of MIF are challenging as both protective and deleterious consequences have been reported [18], [30]–[32].…”

Effects of eplerenone on the activation of matrix metalloproteinase-2 stimulated by high glucose and interleukin-1β in human cardiac fibroblasts

“…Another study also showed that hyperglycemic myocardial damage was mediated by proinflammatory cytokines (Yu et al, 2011). Furthermore, exposure to HG was found to enhance MMP-1 expression of macrophages in response to inflammatory stimuli (Maldonado et al, 2004).…”

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

“…In experimental STZ‐induced T1D models of diabetic cardiomyopathy, NF‐κB activation was shown to be correlated with the increased release of IL‐1β and TNF‐α 113, 114, 115. Moreover, elevated levels of these two pro‐inflammatory cytokines have been found in the circulation and hearts of patients with T2D 116. In fact, several studies report a strong correlation between the characteristic hallmarks of diabetic cardiomyopathy and the levels NF‐κB and cytokines 113.…”

“…This, in turn, drives the production of extracellular matrix (ECM) proteins in the heart, including collagen, fibronectin and proteoglycans, leading to fibrosis, LV remodelling and stiffness, and reduced relaxation of the heart 108, 117. Moreover, a clinical study showed a correlation between macrophage inhibitory factor and the development of diastolic dysfunction in diabetic patients 116. This is of interest as one of the glucagon‐like peptide 1 (GLP‐1) agonists, exendin‐4, a drug class primarily employed in the clinic due to its inherent ability to lower blood glucose, was shown to attenuate adverse cardiac remodelling in diabetic mice, specifically by reducing inflammation, independent of its known glucose‐lowering actions 118…”