Exendin‐4 protects the hearts of rats from ischaemia/reperfusion injury by boosting antioxidant levels and inhibition of JNK/p⁶⁶Shc/NADPH axis

Abstract

Exendin-4, a glucagon-like peptide-1 receptor agonist, was shown to protect against cardiac ischaemia/reperfusion (I/R) injury by suppressing oxidative stress. p 66 Shc, a pro-oxidant and an apoptotic protein, is activated in the infarcted left ventricles (LVs) after induction of I/R. This study investigated if the cardiac protective effect of Exendin-4 against I/R injury in rats involves inhibition of p 66 Shc and to determine the underlying mechanisms behind this. Adult male rats (n = 12/group) were divided into four groups as a sham, a sham + Exendin-4, an I/R, and an I/R + Exendin-4. Exendin-4 was administered to rats 7 days before the induction of I/R. Ischaemia was induced by ligating the left anterior descending (LAD) coronary artery for 40 minutes followed by reperfusion for 10 minutes. The infarct myocardium was used for further analysis. Exendin-4 significantly reduced infarct area (by 62%), preserved LV function and lowered serum levels of LDH and CK-MB in I/R-induced rats. Also, it significantly reduced LV levels of ROS and MDA and protein levels of cytochrome-c and cleaved caspase-3 but significantly increased levels of glutathione (GSH) and manganese superoxide dismutase (MnSOD) in LVs of I/R rats indicating antioxidant and anti-apoptotic effects. Furthermore, it inhibited JNK and p 66 Shc activation and downregulated protein levels of p 66 Shc and NADPH oxidase with no effect on protein levels/activity of p53 and PKCβII. Of note, Exendin-4 also increased GSH and MnSOD in LVs of control rats. In conclusion, Exendin-4 cardioprotective effect in I/R hearts is mediated mainly by antioxidant effect and inhibition of JNK/P 66 Shc/ NADPH oxidase.

Fenugreek Seed Galactomannan Aqueous and Extract Protects against Diabetic Nephropathy and Liver Damage by Targeting NF-κB and Keap1/Nrf2 Axis

“…The levels of ROS/RNS in tissue lysate were measured using a DCF-based kit (#ab238535; Abcam, Cambridge, CB2 0AX, UK) and as previously used by others [ 42 , 43 , 44 ]. Homogenates levels of malondialdehyde (MDA) were measured using special rat assay kits (#10009055, Cayman, Ann Arbor, MI, USA) as validated previously in our labs and described previously by others [ 45 , 46 , 47 , 48 ]. The other rat-specific ELISA kits were used to measure the homogenate levels of superoxide dismutase (SOD) (#MBS036924, MyBioSource, San Diego, CA, USA); tumor necrosis factor-alpha (TNF-α) (#BMS622, ThermoFisher, Waltham, MA, USA), and interleukine-6 (IL-6) (#R6000B, R&D System, Minneapolis, MN, USA).…”

GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential

“…Exendin-4 inhibits the remodeling in the remote myocardium of rats following acute MI by attenuating β-catenin activation and activating glycogen synthase kinase-3, β-arrestin-2 and protein phosphatase 2A [12]. In addition, exendin-4 protects against cardiac ischemia/reperfusion injury in rats by enhancing antioxidant levels and inhibiting c-Jun NH2-terminal kinase (JNK)/p 66 Shc/NADPH oxidase axis [13]. GLP-1RAs, such as lixisenatide, not only rely on β-cell function and glucagon suppression, but also assist to lower glucose by other (insulin-independent) mechanisms such as delayed gastric emptying, underlying the clinical utility of GLP-1RAs as adjuvant therapy to basal insulin in longstanding T2DM [14].…”

Roles of Reactive Oxygen Species in Biological Behaviors of Prostate Cancer

“…Oxidative stress induces ser36 phosphorylation to trigger p66Shc activation, which, in turn, promotes electron transfer from cytochrome c to oxygen, thereby increasing the generation of hydrogen peroxide [ 41 , 42 ]. p66shc also leads to ROS generation by increasing NOXs levels or impairing intracellular antioxidant levels indirectly through inhibiting the activities of FOXO transcription factors [ 43 ]. Clinical prostate tumors show higher levels of p66Shc, relative to adjacent noncancerous specimens, which implies its vital tumorigenic role [ 44 ].…”