Inhibition of cathepsin S attenuates myocardial ischemia/reperfusion injury by suppressing inflammation and apoptosis.

Abstract

Myocardial ischemia/reperfusion (I/R) injury leads to high mortality and morbidity due to the incomplete understanding of the underlying mechanism and the consequent lack of effective therapy. The present study revealed and validated key candidate genes in relation to inflammation and apoptosis pathways underlying myocardial I/R injury. Cathepsin S was identified as the top hub protein based on the protein-protein interaction analysis, and, thus, its role during myocardial I/R injury was further investigated. Myocardial I/R in mice resulted in significantly increased levels of myocardial injury biomarkers (cardiac troponin I, lactic dehydrogenase, and creatinine kinase-MB) and inflammatory cytokines (interleukin-1β [IL-1β], IL-6, and tumor necrosis factor-α), elevated apoptosis rate, and upregulated protein expression of cleaved caspase-8, cleaved caspase-3, and cleaved poly ADP-ribose polymerase. These abovementioned changes were blocked by two different selective cathepsin S inhibitors, LY3000328 or MIV-247. Moreover, Kaplan-Meier survival plot showed that cathepsin S inhibition improved 21-day survival rate following myocardial I/R injury. This study demonstrated that the inhibition of cathepsin S alleviated myocardial I/R-induced injury by suppressing inflammation and apoptosis, which may be used in clinical applications of cardioprotection.

• Authors: Ke Peng, Hong Liu, Bin Yan, Xiao-Wen Meng, Shao-Yong Song, Fu-Hai Ji, Zhengyuan Xia
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 236 Issue 2 Pg. 1309-1320 (02 2021) ISSN: 1097-4652 [Electronic] United States
• PMID: 32657442 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Wiley Periodicals LLC.

Chemical References

• Benzopyrans
• Carbamates
• Cardiotonic Agents
• LY3000328
• Cathepsins
• cathepsin S

Topics

• Animals
• Animals, Newborn
• Apoptosis (drug effects)
• Benzopyrans (pharmacology)
• Carbamates (pharmacology)
• Cardiotonic Agents (pharmacology)
• Cathepsins (antagonists & inhibitors, genetics)
• Disease Models, Animal
• Gene Expression Regulation, Developmental (drug effects)
• Humans
• Inflammation (drug therapy, genetics, pathology)
• Mice
• Myocardial Infarction (drug therapy, genetics, pathology)
• Protein Interaction Maps (drug effects)
• Rats
• Reperfusion Injury (drug therapy, genetics, pathology)