Aims: Several recent reports have shown irisin protects the heart against ischemia/ reperfusion injury. However, the effect of irisin on I/R injury in diabetic mice has not been described. The present study was designed to investigate the role of irisin in myocardial ischemia-reperfusion (MI/R) injury in diabetic mice. Methods: A mouse model of diabetes was established by feeding wild type or genemanipulated adult male mice with a high-fat diet. All the mice received intraperitoneal injection of irisin or PBS. Thirty minutes after injection, mice were subjected to 30 min of myocardial ischemia followed by 3h (for cell apoptosis and protein determination), 24 h (for infarct size and cardiac function). Results: Knockout of gene FNDC5 augmented MI/R injury in diabetic mice, while irisin treatment attenuated MI/R injury, improved cardiac function, cellular ATP biogenetics, mitochondria potential, and impaired mitochondrion-related cell death. More severely impaired AMPK pathway was observed in diabetic FNDC5-/mice received MI/R. Knockout of gene AMPK blocks the beneficial effects of irisin on MI/R injury, cardiac function, cellular ATP biogenetics, mitochondria potential, and mitochondrion-related cell death. Conclusions: Our present study demonstrated that irisin improves the mitochondria function and attenuates MI/R injury in diabetic mice through AMPK pathway.

Objective: To investigate the potential effect of IP7 on the autophagy and apoptosis of bone marrow mesenchymal stem cells (BM-MSCs) caused by hypoxia. Methods: BM-MSCs isolated from adult male C57BL/6 mice were exposed to normoxic condition and hypoxic stress for 6 h, 12 h, and 24 h, respectively. Then, flow cytometry detected the characteristics of BM-MSCs. Furthermore, N6-(p-nitrobenzyl) purine (TNP) was administrated to inhibit inositol pyrophosphates (IP7). TUNEL assay determined the apoptosis in BM-MSCs with hypoxia. Meanwhile, RFP-GFP-LC3 plasmid transfection and transmission microscope was used for measuring autophagy. In addition, Western blotting assay evaluated protein expressions. Results: Hypoxic injury increased the autophagy and apoptosis of BM-MSCs. At the same time, hypoxic injury enhanced the production of IP7. Moreover, hypoxia decreased the activation of Akt/mTOR signaling pathway. At last, TNP (inhibitor of IP7) repressed the increased autophagy and apoptosis of BM-MSCs under hypoxia. Conclusion: The present study indicated that hypoxia increased autophagy and apoptosis via IP7-mediated Akt/mTOR signaling pathway of BM-MSCs. It may provide a new potential therapy target for myocardial infarction (MI).

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Purpose: NLRP3 inflammasome mediates myocardial ischemia/reperfusion (MI/R) injury and diabetic vascular endothelia dysfunction. However, the role of NLRP3 inflammasome in MI/R injury with diabetes has not been fully described. Irisin plays an important role in anti-inflammation and improves endothelial function in type 2 diabetes. The current study aimed to investigate the effect of irisin on regulating NLRP3 inflammasome activation in diabetic vascular endothelia dysfunction. Methods: Cardiac microvascular endothelial cells (CMECs) were cultured and subjected to high glucose/high fat (HG/HF) receiving hypoxia/reoxygenation (H/R) with irisin incubation or not. Then, apoptosis, viability, migration, NO secretion, and inflammasome activation were examined. Results: The hypoxic CMECs exhibited increased apoptosis, impaired viability, and migration, even decreased NO secretion and enhanced inflammasome activation. Moreover, irisin incubation decreased NLRP3 activation and attenuated cell injury in HG/HF cultured CMECs subjected to H/R injury, which was abolished by NLRP3 inflammasome activation. Meanwhile, NLRP3 inflammasome siRNA also attenuated H/R injury in CMECs under HG/HF condition. Conclusion:The current study demonstrated for the first time that irisin inhibits NLRP3 inflammasome activation in CMECs as a novel mechanism in myocardial ischemia/reperfusion injury in diabetes.