Upregulated hepatokine fetuin B aggravates myocardial ischemia/reperfusion injury through inhibiting insulin signaling in diabetic mice.
Abstract
Patients with type 2 diabetes mellitus (T2DM) are more susceptible to acute myocardial ischemia/reperfusion (MI/R) injury. However, the mechanism remains largely elusive. Clinical observation showed that high levels of hepatokine fetuin-B (FetB) in plasma are significantly associated with both diabetes and coronary artery diseases. This study was aimed to determine whether FetB mostly derived from liver exacerbates MI/R-induced injury and the underlying mechanisms in T2DM. Mice were given high-fat diet and streptozotocin to induce T2DM model and subjected to 30 min MI followed by reperfusion. Diabetes caused increased hepatic FetB expression and greater myocardial injury as evidenced by increased apoptosis and myocardial enzymes release following MI/R. In T2DM hearts, insulin-induced phosphorylations of insulin receptor substrate 1 at Tyr608 site and Akt at Ser473 site and glucose transporter 4 membrane translocation were markedly reduced. Interaction between FetB and insulin receptor-β subunit (IRβ) was enhanced assessed by immunoprecipitation analysis. More importantly, FetB knockdown via AAV9 alleviated MI/R injury and improved cardiac insulin-induced signaling in T2DM mice. Conversely, upregulation of FetB in normal mice ca...Continue Reading
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