title: Neutrophil TRPM2 channels are implicated in the exacerbation of myocardial ischaemia/reperfusion injury.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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 H(2)O(2) and leukotriene B(4) (LTB(4)) increased intracellular Ca(2+) concentration and their adhesion to endothelial cells in Trpm2(+)(/+) but not in Trpm2(-/-)PMNs.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathophysiology,  Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555,  Japan.
authors.forename: Toshihito
authors.initials: T
authors.lastname: Hiroi
authors.forename: Teruaki
authors.initials: T
authors.lastname: Wajima
authors.forename: Takaharu
authors.initials: T
authors.lastname: Negoro
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ishii
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Nakano
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kiuchi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Shunichi
authors.initials: S
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007975:Leukotriene B4 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000209:etiology; D015428:Myocardial Reperfusion Injury / Q000209:etiology*; D009504:Neutrophils / Q000502:physiology*; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D016277:Ventricular Function, Left
chemical_list: D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D007975:Leukotriene B4; D006861:Hydrogen Peroxide; D002118:Calcium