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Life Sci ; 233: 116631, 2019 Sep 15.
Article in English | MEDLINE | ID: mdl-31278945

ABSTRACT

AIMS: Prior to reperfusion, Calpains remain inactive due to the acidic pH and elevated ionic strength in the ischemic myocardium; but Calpain is activated during myocardial reperfusion. The underlying mechanism of Calpain activation in the ischemia-reperfusion (I/R) is yet to be determined. Therefore, the present study aims to investigate the mechanism of Calpain in I/R-induced mice. MAIN METHODS: In order to detect the function of Calpain and the NLRP3/ASC/Caspase-1 axis in cardiomyocyte pyroptosis, endoplasmic reticulum (ER) stress and myocardial function, the cardiomyocytes were treated with hypoxia-reoxygenation (H/R), and NLRP3 were silenced, Calpain was overexpressed and Caspase-1 inhibitors were used to determine cardiomyocyte pyroptosis. The results obtained from the cell experiments were then verified with an animal experiment in I/R mice. KEY FINDINGS: There was an overexpression in Calpain, ASC, NLRP3, GRP78 and C/EBP homologous protein (CHOP) in cardiomyocytes following H/R. A significant increase was witnessed in lactic acid dehydrogenase (LDH) activity, cardiomyocyte pyroptosis rate, Calpain activity, reactive oxygen species (ROS) concentration, as well as activation of ER stress in cardiomyocytes after H/R. However, opposing results were observed in H/R cardiomyocytes that received siRNA Calpain, siRNA NLRP3 or Caspase-1 inhibitor treatment. Overall, the results obtained from the animal experiment were consistent with the results from the cell experiment. SIGNIFICANCE: The silencing of Calpain suppresses the activation of the NLRP3/ASC/Caspase-1 axis, thus inhibiting ER stress in mice and improving myocardial dysfunction induced by I/R, providing a novel therapeutic pathway for I/R.


Subject(s)
Amino Acid Transport System y+/antagonists & inhibitors , Calpain/antagonists & inhibitors , Caspase 1/chemistry , Endoplasmic Reticulum Stress , Myocardial Reperfusion Injury/prevention & control , Myocytes, Cardiac/pathology , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Amino Acid Transport System y+/genetics , Amino Acid Transport System y+/metabolism , Animals , Calpain/genetics , Calpain/metabolism , Caspase 1/genetics , Caspase 1/metabolism , Cells, Cultured , Endoplasmic Reticulum Chaperone BiP , Inflammasomes , Male , Mice , Mice, Inbred C57BL , Myocardial Reperfusion Injury/etiology , Myocardial Reperfusion Injury/pathology , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , RNA, Small Interfering/genetics
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