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.
Highlights
Glucagon-like peptide-1 (GLP-1) is an intestinal hormone secreted in a nutrient-dependent manner that stimulates insulin secretion and inhibits glucagon secretion and gastric emptying, resulting in reduced post-prandial hyperglycemia [1]
Studies addressing the plasma-membrane localization of glucagon-like peptide-1 receptor (GLP-1R) are not fully known and the impact of caveolae and Cav-3 on GLP-1-induced cardiac protection has not been investigated. We hypothesized that both caveolae and Cav-3 are a critical component of GLP-1-induced cardiac protection and that coordination of protective signaling is dependent on the co-localization of Cav-3 and GLP-1R
Exendin-4 induces cardiac protection in cardiac myocytes (CM) CM were administered with various concentration of Ex-4 and simulated ischemia/reperfusion (SI/R) (Figure 1A)
Summary
Glucagon-like peptide-1 (GLP-1) is an intestinal hormone secreted in a nutrient-dependent manner that stimulates insulin secretion and inhibits glucagon secretion and gastric emptying, resulting in reduced post-prandial hyperglycemia [1]. GLP-1 has been shown to reduce an infarct size in both in vitro and in vivo animal models of cardiac ischemia/ reperfusion injury [5,6,7] and exendin-4 (Ex-4), an exogenous GLP-1R agonist isolated form the Gila monster lizard [8], has reported to have very similar effects [4,9,10]. We have shown that both caveolae and Cav-3 were essential in cardiac protection against ischemia/ reperfusion in the animal model [14,15,16,17]. Exendin-4, an exogenous glucagon-like peptide-1 receptor (GLP-1R) agonist, protects the heart from ischemia/reperfusion injury. 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)
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