Exendin-4 ameliorates cardiac ischemia/reperfusion injury via caveolae and caveolins-3
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.
Insights
Caveolae and caveolin-3 are essential for exendin-4 to protect the heart from ischemia/reperfusion injury. Disruption of caveolae or absence of caveolin-3 abolishes exendin-4's cardioprotective effects.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cellular Physiology
Background:
- Exendin-4, a glucagon-like peptide-1 receptor agonist, offers cardiac protection against ischemia/reperfusion (I/R) injury.
- The underlying mechanisms of exendin-4's cardioprotective effects remain unclear.
- Caveolae and their scaffolding proteins, caveolins, are implicated in cardiac protection.
Purpose of the Study:
- To investigate the role of caveolae and caveolin-3 in exendin-4-mediated cardioprotection.
- To test the hypothesis that caveolae and caveolin-3 are critical for exendin-4's protective effects.
- Utilizing in vitro and in vivo models, including caveolin-3 knockout mice.
Main Methods:
- Cardiac myocytes were treated with exendin-4 and subjected to simulated ischemia/reperfusion (SI/R).
- Caveolae formation was disrupted using methyl-β-cyclodextrin (MβCD).
- In vivo studies assessed infarct size and cardiac troponin levels in control and caveolin-3 knockout mice.
Main Results:
- Exendin-4 significantly reduced cell death and apoptosis in cardiac myocytes following SI/R.
- Methyl-β-cyclodextrin treatment abolished exendin-4's protective effects on cardiac myocytes.
- Exendin-4 reduced infarct size and cardiac troponin levels in vivo, but this protection was lost in caveolin-3 knockout mice.
Conclusions:
- Caveolae and caveolin-3 are indispensable for exendin-4's cardioprotective effects against ischemia/reperfusion injury.
- These findings highlight the critical role of the caveolae/caveolin-3 complex in mediating exendin-4's benefits.
- Targeting caveolae and caveolin-3 may offer novel therapeutic strategies for cardiac protection.
