The Role of Pyroptosis in Ischemic and Reperfusion Injury of the Heart.

Abstract

While ischemia itself can kill heart muscle, much of the infarction after a transient period of coronary artery occlusion has been found to result from injury during reperfusion. Here we review the role of inflammation and possible pyroptosis in myocardial reperfusion injury. Current evidence suggests pyroptosis's contribution to infarction may be considerable. Pyroptosis occurs when inflammasomes activate caspases that in turn cleave off an N-terminal fragment of gasdermin D. This active fragment makes large pores in the cell membrane thus killing the cell. Inhibition of inflammation enhances cardiac tolerance to ischemia and reperfusion injury. Stimulation of the purinergic P2X7 receptor and the β-adrenergic receptor and activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) by toll-like receptor (TLR) agonists are all known to contribute to ischemia/reperfusion (I/R) cardiac injury through inflammation, potentially by pyroptosis. In contrast, stimulation of the cannabinoid CB2 receptor reduces I/R cardiac injury and inhibits this pathway. MicroRNAs, Akt, the phosphate and tension homology deleted on chromosome 10 protein (PTEN), pyruvate dehydrogenase and sirtuin-1 reportedly modulate inflammation in cardiomyocytes during I/R. Cryopyrin and caspase-1/4 inhibitors are reported to increase cardiac tolerance to ischemic and reperfusion cardiac injury, presumably by suppressing inflammasome-dependent inflammation. The ambiguity surrounding the role of pyroptosis in reperfusion injury arises because caspase-1 also activates cytotoxic interleukins and proteolytically degrades a surprisingly large number of cytosolic enzymes in addition to activating gasdermin D.

• Authors: Sergey V Popov, Leonid N Maslov, Natalia V Naryzhnaya, Alexandr V Mukhomezyanov, Andrey V Krylatov, Sergey Y Tsibulnikov, Vyacheslav V Ryabov, Michael V Cohen, James M Downey
• Journal: Journal of cardiovascular pharmacology and therapeutics (J Cardiovasc Pharmacol Ther) Vol. 26 Issue 6 Pg. 562-574 (11 2021) ISSN: 1940-4034 [Electronic] United States
• PMID: 34264787 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Caspase Inhibitors
• GSDMD protein, human
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Phosphate-Binding Proteins
• Pore Forming Cytotoxic Proteins

Topics

• Animals
• Caspase Inhibitors (pharmacology)
• Humans
• Myocardial Ischemia (drug therapy, physiopathology)
• Myocardial Reperfusion Injury (drug therapy, physiopathology)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Phosphate-Binding Proteins
• Pore Forming Cytotoxic Proteins
• Pyroptosis
• Rats