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

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.

• Authors: Yasuo M Tsutsumi, Rie Tsutsumi, Eisuke Hamaguchi, Yoko Sakai, Asuka Kasai, Yoshihiro Ishikawa, Utako Yokoyama, Katsuya Tanaka
• Journal: Cardiovascular diabetology (Cardiovasc Diabetol) Vol. 13 Pg. 132 (Sep 07 2014) ISSN: 1475-2840 [Electronic] England
• PMID: 25194961 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Caveolin 3
• Hypoglycemic Agents
• Peptides
• Venoms
• Exenatide

Topics

• Animals
• Caveolae (metabolism)
• Caveolin 3 (metabolism)
• Exenatide
• Hypoglycemic Agents (pharmacology)
• Ischemia (metabolism, prevention & control)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Reperfusion Injury (metabolism, prevention & control)
• Myocardium (metabolism)
• Myocytes, Cardiac (drug effects, metabolism)
• Peptides (pharmacology)
• Rats, Wistar
• Venoms (pharmacology)