Ischemia-Reperfusion Injury Leads to Distinct Temporal Cardiac Remodeling in Normal versus Diabetic Mice

Abstract

Diabetes is associated with higher incidence of myocardial infarction (MI) and increased propensity for subsequent events post-MI. Here we conducted a temporal analysis of the influence of diabetes on cardiac dysfunction and remodeling after ischemia reperfusion (IR) injury in mice. Diabetes was induced using streptozotocin and IR performed by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for up to 42 days. We first evaluated changes in cardiac function using echocardiography after 24 hours reperfusion and observed IR injury significantly decreased the systolic function, such as ejection fraction, fractional shortening and end systolic left ventricular volume (LVESV) in both control and diabetic mice. The longitudinal systolic and diastolic strain rate were altered after IR, but there were no significant differences between diabetic mice and controls. However, a reduced ability to metabolize glucose was observed in the diabetic animals as determined by PET-CT scanning using 2-deoxy-2-(18F)fluoro-D-glucose. Interestingly, after 24 hours reperfusion diabetic mice showed a reduced infarct size and less apoptosis indicated by TUNEL analysis in heart sections. This may be explained by increased levels of autophagy detected in diabetic mice hearts. Similar increases in IR-induced macrophage infiltration detected by CD68 staining indicated no change in inflammation between control and diabetic mice. Over time, control mice subjected to IR developed mild left ventricular dilation whereas diabetic mice exhibited a decrease in both end diastolic left ventricular volume and LVESV with a decreased intraventricular space and thicker left ventricular wall, indicating concentric hypertrophy. This was associated with marked increases in fibrosis, indicted by Masson trichrome staining, of heart sections in diabetic IR group. In summary, we demonstrate that diabetes principally influences distinct IR-induced chronic changes in cardiac function and remodeling, while a smaller infarct size and elevated levels of autophagy with similar cardiac function are observed in acute phase.

Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes

“…Collectively these findings indicate that autophagy compensates (incompletely) for the lack of energy in an effort to maintain cardiac function in type 1 DM. Our findings in the type 1 DM model as well as those of Eguchi et al 24 are consistent with this idea. However, diametrically opposite reports do exist.…”

Glucagon-Like Peptide-1 Protects Against Cardiac Microvascular Injury in Diabetes via a cAMP/PKA/Rho-Dependent Mechanism

“…Whole-body 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET)/computed tomography (CT) scanning was performed using an animal PET/CT scanner (Mediso Nano PET/CT) described previously (21). The rats were maintained under fasting condition for 12–14 h, and fasting blood glucose levels were maintained between 6.0 and 7.5 mmol/L.…”

Myocardial autophagic energy stress responses—macroautophagy, mitophagy, and glycophagy

“…Since our first report of increased cardiac autophagy in the type 2 diabetic fructose-fed mouse (59), the experimental literature in this field has expanded considerably, but it is not yet possible to synthesize a comprehensive understanding. Relying on a variable selection of molecular tools, states of increased (4,12,49,50,59,61,78,93,102), unchanged (47,48,57,62), and decreased (6,23,28,29,73,82,101,103,104,110) basal cardiac autophagy activity have all been reported in diabetic/ insulin resistant contexts (see Table 1). These discrepancies are not necessarily attributable to the different models of diabetes, since contrasting findings have been observed within the same diabetic model [e.g., STZ-mouse: increased LC3BII (12) vs. decreased LC3BII (103)].…”