The role of ADAM protease in the tyrosine kinase-mediated trigger mechanism of ischemic preconditioning.
OBJECTIVE
The aim of this study was to determine the role of an a disintegrin and metalloprotease (ADAM) in tyrosine kinase-mediated mechanisms of ischemic preconditioning (PC).


RESULTS
In isolated rabbit hearts, PC was performed with two cycles of 5 min ischemia/5 min reperfusion and infarction was induced by 30 min global ischemia/2 h reperfusion. Translocation of protein kinase C- (PKC-) and tyrosine phosphorylation in the tissue and TNF-alpha in coronary effluent were determined by immunoblotting. PC reduced infarct size from 55.1+/-6.8% of the left ventricle to 24.4+/-5.2%, and this protection was mimicked by pretreatment with 100 nM angiotensin II. Both the PC effect and angiotensin II-induced protection were abolished by genistein and by 10 microM KB-R7785 (KBR), an inhibitor of ADAM12/17, but not by a lower ADAM12-selective dose (1 microM) of KBR. AG1478, an inhibitor of EGF receptor tyrosine kinase, did not inhibit protection afforded by PC. PC provoked release of TNF-alpha into the coronary effluent, which was abolished by 10 microM KBR but not by 1 microM of KBR or calphostin C, a PKC inhibitor. PKC- translocation by PC was not affected by KBR. PC induced tyrosine phosphorylation of 60 and 90 kDa proteins, and this phosphorylation was abolished by 10 microM KBR but not by calphostin C. Pretreatment with TNF-alpha limited infarct size to 16.7+/-3.7% and induced tyrosine phosphorylation of a 60 kDa protein.


CONCLUSIONS
The results support the hypothesis that an ADAM contributes to the triggering of a tyrosine kinase-mediated and PKC-independent pathway of PC. The ADAM responsible for this tyrosine kinase-mediated pathway is likely to be ADAM17, which sheds TNF-alpha.
Ichikawa
Yoshihiko
Y
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan.
Miura
Tetsuji
T
Nakano
Atsushi
A
Miki
Takayuki
T
Nakamura
Yuichi
Y
Tsuchihashi
Kazufumi
K
Shimamoto
Kazuaki
K
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D019833:Genistein / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D015151:Immunoblotting / Q000379:methods; D019157:Ischemic Preconditioning, Myocardial; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009203:Myocardial Infarction / Q000201:enzymology* / Q000517:prevention & control; D009281:Naphthalenes / Q000494:pharmacology; D010477:Perfusion; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000494:pharmacology
D006877:Hydroxamic Acids; C107086:KB R7785; D009281:Naphthalenes; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C058819:calphostin C; D005998:Glycine