Journal
CARDIOVASCULAR RESEARCH
Volume 97, Issue 2, Pages 271-281Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvs332
Keywords
TRPM2; Heart; Reperfusion injury; Neutrophils; Calcium
Categories
Funding
- KAKENHI [21590104]
- High-Tech Research Center Project for Private Universities
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Grants-in-Aid for Scientific Research [24591471, 23590474, 21590104] Funding Source: KAKEN
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Transient receptor potential melastatin 2 (TRPM2) highly expressed in immunocytes is a Ca-2-permeable non-selective cation channel activated by oxidative stress. Myocardial ischaemia/reperfusion (I/R) injury is characterized by acute inflammation associated with the augmentation of oxidative stress. We hypothesized that TRPM2 is implicated in the exacerbation of myocardial I/R injury. Wild-type (Trpm2(/)) and Trpm2 knockout (Trpm2(/)) mice were subjected to ligation of the left main coronary artery followed by reperfusion. Myocardial infarction following I/R, but not ischaemia alone, was reduced more in Trpm2(/)mice than in Trpm2(/) mice and cardiac contractile functions were also improved in Trpm2(/)mice. TRPM2 was highly expressed in the polymorphonuclear leucocytes (PMNs) rather than in the heart. The number of neutrophils and myeloperoxidase (MPO) activity in the reperfused area following ischaemia was lowered in Trpm2(/) mice. When Trpm2(/) or Trpm2(/) PMNs were administered to the Trpm2(/) heart ex vivo through the perfusate or in vivo by iv injection, Trpm2(/) PMNs produced enlargement of the infarct size. Following in vitro regional I/R, a pharmacological inhibitor of TRPM2 reduced the infarct size. The combination of H2O2 and leukotriene B-4 (LTB4) increased intracellular Ca-2 concentration and their adhesion to endothelial cells in Trpm2(/) but not in Trpm2(/)PMNs. These findings indicate that neutrophil TRPM2 is implicated in the exacerbation of myocardial reperfusion injury. Accumulation of neutrophils in the reperfused area mediated by TRPM2 activation is likely to play a crucial role in myocardial I/R injury.
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