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Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2014

Open Access 01-12-2014 | Original investigation

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

Authors: Yasuo M Tsutsumi, Rie Tsutsumi, Eisuke Hamaguchi, Yoko Sakai, Asuka Kasai, Yoshihiro Ishikawa, Utako Yokoyama, Katsuya Tanaka

Published in: Cardiovascular Diabetology | Issue 1/2014

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Abstract

Background

Exendin-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).

Methods

Myocytes 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.

Results

Exendin-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).

Conclusions

We conclude that caveolae and caveolin-3 are critical for exendin-4 induced protection of the heart from ischemia/reperfusion injury.
Appendix
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Metadata
Title
Exendin-4 ameliorates cardiac ischemia/reperfusion injury via caveolae and caveolins-3
Authors
Yasuo M Tsutsumi
Rie Tsutsumi
Eisuke Hamaguchi
Yoko Sakai
Asuka Kasai
Yoshihiro Ishikawa
Utako Yokoyama
Katsuya Tanaka
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2014
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-014-0132-9

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