ZP2495 Protects against Myocardial Ischemia/Reperfusion Injury in Diabetic Mice through Improvement of Cardiac Metabolism and Mitochondrial Function: The Possible Involvement of AMPK‐FoxO3a Signal Pathway

Abstract

Coronary heart disease patients with type 2 diabetes were subject to higher vulnerability for cardiac ischemia-reperfusion (I/R) injury. This study was designed to evaluate the impact of ZP2495 (a glucagon-GLP-1 dual-agonist) on cardiac function and energy metabolism after myocardial I/R injury in db/db mice with a focus on mitochondrial function. C57BLKS/J-lepr+/lepr+ (BKS) and db/db mice received 4-week treatment of glucagon, ZP131 (GLP-1 receptor agonist), or ZP2495, followed by cardiac I/R injury. The results showed that cardiac function, cardiac glucose metabolism, cardiomyocyte apoptosis, cardiac mitochondrial morphology, and energetic transition were improved or ameliorated by ZP2495 to a greater extent than that of glucagon and ZP131. In vitro study showed that ZP2495, rather than glucagon, alleviated mitochondrial depolarization, cytochrome C release, and mitochondria ROS generation in neonatal rat ventricular myocytes subjected to high-glucose and simulated I/R injury conditions, the effects of which were weaker in the ZP131 group. Furthermore, the expressions of Akt, FoxO3a, and AMPK phosphorylation were elevated by ZP2495 to a greater extent than that of ZP131. In conclusion, ZP2495 may contribute to the improvement of cardiac function and energy metabolism in db/db mice after myocardial I/R injury by improving mitochondrial function possibly through Akt/FoxO3a and AMPK/FoxO3a signal pathways.

Treatment with placental growth factor attenuates myocardial ischemia/reperfusion injury

“…[ 35 , 36 ] The activation of Akt/FoxO3a has been reported to improve mitochondrial function after MIRI. [ 37 ] The cleaved caspase-3 is the terminal common effector of the apoptotic pathway, and the activation of Akt is a major negative regulator of apoptosis. [ 22 , 38 ] We found PlGF treatment enhanced the phosphorylation of Akt, GSK-3 and FoxO3a and inhibited the activation of caspase-3 after reperfusion.…”

TRPA1 Promotes Cardiac Myofibroblast Transdifferentiation after Myocardial Infarction Injury via the Calcineurin-NFAT-DYRK1A Signaling Pathway

“…The protein concentration was determined using the BCA method (Thermo Fisher Scientific, USA). Western blotting was performed following a standard protocol, as described previously [24]. The following primary antibodies were used: anti-TRPA1 (110 kDa, 1 : 1000, rabbit polyclonal, Novus Biologicals, USA), anti-Postn (93 kDa, 1 : 1000, rabbit polyclonal, Novus Biologicals, USA), anti-NFATc3 (115 kDa, 1 : 1000, rabbit polyclonal, Abcam, USA), anti-DYRK1A (86 kDa, 1 : 1000, rabbit polyclonal, Abcam, USA), anti- β -actin (43 kDa, 1 : 1,000, rabbit polyclonal, Santa Cruz Biotechnology Inc., USA), anti-GAPDH (36 kDa, 1 : 1000, rabbit monoclonal, Abcam, USA), and anti-Histone H3 (15 kDa, 1 : 1000, rabbit monoclonal, Abcam, USA).…”

Network Pharmacology/Metabolomics‐Based Validation of AMPK and PI3K/AKT Signaling Pathway as a Central Role of Shengqi Fuzheng Injection Regulation of Mitochondrial Dysfunction in Cancer‐Related Fatigue

“…Previous research has found that AKT activity is inhibited by the phosphorylation of FoxO3a at the Ser253 site [41]. However, the results of these experiments have shown opposite expression results for Foxo3a phosphorylation at Ser523 and Ser413 sites (Figure 7(b)).…”