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Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity

Xi-Ming Yang1, Michael V Cohen1,2, Sarah Sayner1

  • 1Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.

International Journal of Molecular Sciences
|February 25, 2023
PubMed

Insights

Caspase-1/4 inhibition limits reperfusion injury by targeting early injury mechanisms. Combining caspase-1/4 inhibition with ischemic preconditioning offers additive protection against heart attack damage.

Area of Science:

  • Cardiovascular Research
  • Molecular and Cellular Biology
  • Inflammation and Immunity

Background:

  • Reperfusion injury significantly contributes to myocardial damage after ischemia.
  • Caspase-1/4 activation is implicated in the pathogenesis of reperfusion injury.
  • Understanding the precise role of caspase-1/4 is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the role of caspase-1/4 in myocardial reperfusion injury.
  • To identify the upstream activators and downstream effectors of caspase-1/4 in this context.
  • To explore combination therapies for enhanced protection against reperfusion injury.

Main Methods:

  • Isolated mouse heart model subjected to global ischemia and reperfusion.
  • Pharmacological inhibition of caspase-1/4 using VRT-043198 and emricasan.
  • Genetic ablation of caspase-1/4, NLRC4 inflammasome, and AC10.
  • Assessment of infarct size (IS) as a primary outcome measure.
  • Evaluation of ischemic preconditioning (IPC) and calpain inhibition.

Main Results:

  • VRT-043198 and emricasan significantly reduced infarct size, an effect replicated in caspase-1/4-knockout hearts.
  • NLRC4 knockout hearts showed no protection, indicating NLRC4 is not the activator.
  • Protection by caspase-1/4 inhibition was limited to the first 10 minutes of reperfusion.
  • Ischemic preconditioning provided protection comparable to caspase-1/4 inhibition.
  • Combined IPC and caspase-1/4 inhibition, or caspase-1/4 inhibition and calpain inhibition, yielded additive protection.

Conclusions:

  • Caspase-1/4 plays a critical role in early reperfusion injury, mediating damage within the first 10 minutes.
  • Calpain activation may contribute to caspase-1/4-mediated injury, potentially by releasing procaspase-1.
  • Combination therapies, such as combining ischemic preconditioning with caspase-1/4 or calpain inhibition, offer superior protection against myocardial reperfusion injury.
Keywords:
AC10VRT-043198calpaincardioprotectioncaspase-1emricasan

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