Exendin-4 ameliorates cardiac ischemia/reperfusion injury via caveolae and caveolins-3

Abstract

BackgroundExendin-4, an exogenous glucagon-like peptide-1 receptor (GLP-1R) agonist, protects the heart from ischemia/reperfusion injury. However, the mechanisms for this protection are poorly understood. Caveolae, sarcolemmal invaginations, and caveolins, scaffolding proteins in caveolae, localize molecules involved in cardiac protection. We tested the hypothesis that caveolae and caveolins are essential for exendin-4 induced cardiac protection using in vitro and in vivo studies in control and caveolin-3 (Cav-3) knockout mice (Cav-3 KO).MethodsMyocytes were treated with exendin-4 and then incubated with methyl-β-cyclodextrin (MβCD) to disrupt caveolae formation. This was then followed by simulated ischemia/reperfusion (SI/R). In addition, cardiac protection in vivo was assessed by measuring infarct size and cardiac troponin levels.ResultsExendin-4 protected cardiac myocytes (CM) from SI/R [35.6 ± 12.6% vs. 64.4 ± 18.0% cell death, P = 0.034] and apoptosis but this protection was abolished by MβCD (71.8 ± 10.8% cell death, P = 0.004). Furthermore, Cav-3/GLP-1R co-localization was observed and membrane fractionation by sucrose density gradient centrifugation of CM treated with MβCD + exendin-4 revealed that buoyant (caveolae enriched) fractions decreased Cav-3 compared to CM treated with exendin-4 exclusively. Furthermore, exendin-4 induced a reduction in infarct size and cardiac troponin relative to control (infarct size: 25.1 ± 8.2% vs. 41.4 ± 4.1%, P < 0.001; troponin: 36.9 ± 14.2 vs. 101.1 ± 22.3 ng/ml, P < 0.001). However, exendin-4 induced cardiac protection was abolished in Cav-3 KO mice (infarct size: 43.0 ± 6.4%, P < 0.001; troponin: 96.8 ± 26.6 ng/ml, P = 0.001).ConclusionsWe conclude that caveolae and caveolin-3 are critical for exendin-4 induced protection of the heart from ischemia/reperfusion injury.

Discrepancy between the Actions of Glucagon-like Peptide-1 Receptor Ligands in the Protection of the Heart against Ischemia Reperfusion Injury

“…Reductions in ROS by Ex-4 and GLP-1 in the protection of cardiomyocytes were also reported previously [53,54]. Nevertheless, it was in a pretreatment procedure, where Ex-4 and GLP-1 (9-36) protected the heart against hypoxic damage [55]. Similar protective effects by decreasing ROS levels were reported previously by our laboratory [56,57].…”

Hyperglycemia-Induced Oxidative Stress Abrogates Remifentanil Preconditioning-Mediated Cardioprotection in Diabetic Rats by Impairing Caveolin-3-Modulated PI3K/Akt and JAK2/STAT3 Signaling

“…Cav-3 is a major isoform of the caveolin family proteins to form cardiomyocyte caveolae [20], serving as a platform to enrich cardioprotective signaling molecules, including PI3K/Akt [53] and JAK/STAT [54]. It has been reported that both caveolae and caveolin-3 are critical for retaining myocardial tolerance to I/R injury [21, 55] and Cav-3 expression is also required for opioid induced cardioprotection [23]. Therefore, any alteration of Cav-3 expression in diabetes may be implicated in the compromised RPC-mediated cardioprotection, and thus, restoring Cav-3 expression should be beneficial to preserve the effectiveness of RPC in diabetes.…”

TIR/BB-loop mimetic AS-1 attenuates cardiac ischemia/reperfusion injury via a caveolae and caveolin-3-dependent mechanism

“…To examine whether AS-1 mediated protection against H/R-induced cell injury was through the caveolae dependent mechanism, we treated the cells with methyl-β-cyclodextrin (MCD) in order to disrupt caveolae 13 before the cells were treated with AS-1. Figure 7A and B showed disruption of caveolae by MCD abolished AS-1-induced protection against H/R-induced injury in H9C2 cardiomyocytes: the levels of cell viability and LDH release in AS-1 plus MCD treated cells were comparable with H/R-stimulated cells.…”