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Updated: May 31, 2026
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Differential roles of GSK-3β during myocardial ischemia and ischemia/reperfusion
Peiyong Zhai1, Sebastiano Sciarretta, Jonathan Galeotti
1Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.
Rationale:
Inhibition of glycogen synthase kinase-3 (GSK-3) protects the heart during ischemia/reperfusion (I/R), yet the underlying mechanisms of cardioprotection afforded by beta isoform-specific inhibition GSK-3 remain to be elucidated.
Objective:
We studied the molecular mechanism mediating the effect of GSK-3β activation/inhibition upon myocardial injury during prolonged ischemia and I/R.
Methods And Results:
Beta isoform-specific inhibition of GSK-3 by dominant negative GSK-3β in transgenic mice (Tg-DnGSK-3β) or in heterozygous GSK-3β knock-out mice (GSK-3β+/-) significantly increased, whereas activation of GSK-3β in constitutively active GSK-3β knock-in mice (βKI) significantly decreased, myocardial ischemic injury after prolonged ischemia. In contrast, inhibition of GSK-3β in Tg-DnGSK-3β or GSK-3β+/- significantly reduced, while activation of GSK-3β in βKI significantly enhanced, myocardial I/R injury. Inhibition of GSK-3β stimulated mTOR signaling and inhibited autophagy through a rapamycin-sensitive (mTOR dependent) mechanism. Rapamycin enhanced autophagy and, at the same time, abolished the effects of GSK-3β inhibition on both prolonged ischemic injury and I/R injury. Importantly, the influence of rapamycin over the effects of GSK-3β inhibition on myocardial injury was reversed by inhibition of autophagy.
Conclusions:
Our results suggest that beta isoform-specific inhibition of GSK-3 exacerbates ischemic injury but protects against I/R injury by modulating mTOR and autophagy.
Insights
Beta isoform-specific inhibition of glycogen synthase kinase-3 (GSK-3) worsens ischemic injury but protects against ischemia/reperfusion (I/R) injury by modulating mTOR and autophagy pathways.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Cellular Signaling
Background:
- Glycogen synthase kinase-3 (GSK-3) inhibition shows cardioprotective effects during ischemia/reperfusion (I/R).
- The specific mechanisms of beta isoform-specific GSK-3 inhibition in cardioprotection require further investigation.
Purpose of the Study:
- To elucidate the molecular mechanisms of GSK-3β activation and inhibition on myocardial injury during prolonged ischemia and I/R.
- To investigate the role of mTOR and autophagy in mediating these effects.
Main Methods:
- Utilized transgenic mice with dominant-negative GSK-3β (Tg-DnGSK-3β) and heterozygous GSK-3β knockout (GSK-3β+/-) mice.
- Employed constitutively active GSK-3β knock-in (βKI) mice to study GSK-3β activation.
- Administered rapamycin to modulate mTOR and autophagy pathways.
Main Results:
- GSK-3β inhibition exacerbated prolonged ischemic injury but reduced I/R injury.
- GSK-3β activation decreased prolonged ischemic injury but enhanced I/R injury.
- GSK-3β inhibition stimulated mTOR signaling and inhibited autophagy in a rapamycin-sensitive manner.
- Rapamycin abolished the effects of GSK-3β inhibition on both injury types, and this was reversed by autophagy inhibition.
Conclusions:
- Beta isoform-specific GSK-3 inhibition worsens ischemic injury while protecting against I/R injury.
- These effects are mediated through the modulation of mTOR signaling and autophagy.
- Targeting GSK-3β offers a potential therapeutic strategy for managing myocardial ischemia and I/R injury.