Cardioprotective effects of exenatide against oxidative stress-induced injury

Abstract

Myocardial ischemia/reperfusion (MI/R) leads to oxidative stress, which may in turn lead to myocardial injury. In the present study, we investigated the effects of exenatide, a glucagon-like peptide-1 (GLP-1) analogue, on oxidative stress-induced injury in vitro and in vivo. In in vitro experiments, H9c2 cells were incubated with exenatide to determine the direct cytoprotective effects of exenatide following exposure to hydrogen peroxide (H2O2). Pre-treatment with exenatide (1 nM), prior to H2O2 exposure, increased cell viability and inhibited H2O2-induced reactive oxygen species (ROS) production. Exenatide also decreased the levels of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in the cultured supernatants, as well as those of malondialdehyde (MDA) in the H9c2 cells and increased the total superoxide dismutase (T-SOD) levels in the H9c2 cells. In in vivo experiments, an animal model of MI/R was induced by coronary occlusion. Pre-treatment with exenatide (10 µg/kg/day) protected the rat hearts from MI/R-induced injury by decreasing the levels of LDH and CK-MB in plasma, increasing the levels of catalase, T-SOD and glutathione peroxidase (GSH-Px) in the heart and decreasing the MDA levels in the rats with MI/R-induced injury. Exenatide also reduced the infarct size and enhanced cardiac function in the rats with MI/R-induced injury. Moreover, pre-treatment with exenatide inhibited cardiomyocyte apoptosis, increased Aktserine473 and Badserine136 phosphorylation and decreased cleaved caspase-3 expression in vitro and in vivo; however, these effects were attenuated by the phosphoinositide 3-kinase (PI3K) inhibitor, LY294002. Our results suggest that exenatide exerts significant cardioprotective effects against oxidative stress-induced injury in vitro and in vivo. The mechanisms involved may be attributed to the scavenging of oxidative stress products, such as ROS, the increase in the concentrations of antioxidant defense enzymes and the inhibition of cardiomyocyte apoptosis. The anti-apoptotic effects of exenatide were, at least in part, associated with the activation of the PI3K/Akt signaling pathway.

Stimulation of glucagon-like peptide-1 receptor through exendin-4 preserves myocardial performance and prevents cardiac remodeling in infarcted myocardium

“…This was supported by another observation in which the GLP-1(28 -36) amide nonapeptide rapidly enters isolated mouse hepatocytes and targets the mitochondria, where it inhibits oxidative stress (35). In addition, it is known that GSH is important for maintaining redox levels of cells and can be used to detect cell death (9). Our results indicate that GLP-1R stimulation prevented the decrease in GSH levels in cells exposed to oxidative stress, implying the role of exendin-4 in attenuating oxidative stress-induced injury.…”

Geniposide Prevents Hypoxia/Reoxygenation-Induced Apoptosis in H9c2 Cells: Improvement of Mitochondrial Dysfunction and Activation of GLP-1R and the PI3K/AKT Signaling Pathway

“…Accumulating evidence has revealed that AKT activation plays a crucial role in the cardioprotective effect after ischemia-reperfusion injury. Activation of the anti-apoptotic signaling pathway PI3K/AKT could regulate Bcl-2, inhibit caspase cascade activation and reduce death gene expression [32]. In our study, the improvement of cell viability and attenuation of cell apoptosis ratio by geniposide pretreatment during H/R were blocked by exendin (9-39) and LY294002 to some extent.…”

“…Physiological levels of ROS/RNS in normal oxidative metabolism play a key homeostatic role in balancing disposal rates of oxidative pressure and enzyme systems in cell proliferation and survival [27][28][29]. As levels of SOD, glutathione, and catalase are less in the cardiac system, excessive production of ROS/RNS triggers oxidative stress and aggravates ischemia-induced cardiomyocyte damage [27,30], further accelerating cardiomyocyte apoptosis and loss [31,32]. Treatment with antioxidant agents or upregulation of endogenous antioxidant enzymes could prevent excessive ROS-caused injury [4,33,34].…”

“…GLP-1R is expressed in various tissues and organs, including the pancreas, gastrointestinal tract, nervous system, blood vessels, and heart [44,45].. Activated GLP-1R mediates the cAMP/ protein kinase A (PKA)/ cAMP-responsive element binding protein (CREB) pathway, resulting in the activation of phosphatidylinositol-3 kinase (PI3K), AKT-protein kinase B (AKT/PKB), and extracellular regulated kinase (ERK1/2) signaling pathway [32,46]. Accumulating evidence has revealed that AKT activation plays a crucial role in the cardioprotective effect after ischemia-reperfusion injury.…”

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

“…A 2 R activation also is necessary for the cardioprotective effects of ischemic postconditioning (20). Stimulating GLP1R and cAMP/PKA signaling also can prevent cardiac myocyte death (18,28). PDE3 appears to be important in regulating β-AR-stimulated cAMP-signaling modules.…”